Medicinal Chemistry — September 2026

• Melittin is potently antimicrobial but too haemolytic to be a lead; the authors built 10-, 15- and 20-mer peptides from repeats of its C-terminal WIKRK segment.
• The 15- and 20-mers adopt β-sheet structure in bacterial-mimetic vesicles, with negligible haemolysis and cytotoxicity and strong activity against bacteria and mycobacteria.
• They were active in an E. coli mouse infection model by intravenous dosing and inhibited transcription and translation, suggesting an intracellular mechanism.

β-Sheet Antimicrobial and Antimycobacterial Peptides with a High Therapeutic Index by Employing the Repeats of a 5-Mer Segment of α-Helical Cytolytic Melittin ↗

• The team probed the δ-position of the 4,5-dihydroxyisoleucine residue in α-amanitin, a residue long assumed to drive RNA polymerase II inhibition.
• Two δ-modified analogs carry handles for direct linker attachment, so conjugation no longer has to go through other positions on the bicyclic peptide.
• Both were converted into trastuzumab conjugates that showed extremely high cytotoxicity on target-expressing cells, supporting these amatoxins as ADC payloads.

Unlocking Potent Amatoxin Antibody−Drug Conjugates Using Structure−Activity Studies on δ-Substituted-γ-Hydroxy Isoleucine ↗

• Existing αvβ6-targeting tracers for pancreatic cancer suffer from modest tumor uptake and fast washout; the authors varied hydrophilic linkers and an albumin-binding moiety, guided by docking and MD.
• The lead, NOTA-Asp2-IPB-αvβ6L, was labeled with 18F, 68Ga and 177Lu and kept high hydrophilicity, target affinity and albumin binding.
• In PET/CT it showed higher tumor uptake and longer retention while keeping favorable pharmacokinetics, supporting a matched imaging–therapy pair.

Albumin-Binding Modification Improves Tumor Retention of Hydrophilic αvβ6-Targeting Radiotheranostic Tracers ↗

• Tris-catecholate siderophore–meropenem conjugates overcame porin-loss and efflux-based carbapenem resistance in P. aeruginosa in an iron-dependent manner.
• The team also vectorized an indole-carboxylate MBL inhibitor, which alone barely works in P. aeruginosa, apparently for permeability reasons.
• The conjugates restored inhibitor activity and reversed meropenem and cefiderocol resistance in MBL-producing clinical isolates, in vitro and in a Galleria mellonella model.

Siderophore-Enabled Delivery of Carbapenem and Metallo-β-Lactamase Inhibitor: A Promising Strategy against Multidrug-Resistant Pseudomonas aeruginosa ↗

• An automated, high-throughput ligand-detected NMR method targets hit triage in medicinal chemistry screening campaigns.
• The approach is framed as enabling rapid, qualitative binding assessment of screening hits at scale.
• Reads as a platform/methodology contribution focused on throughput and workflow automation rather than a single target or chemical series.

Automated High-Throughput Ligand-Detected NMR for Medicinal Chemistry Hit Triage and Binding Assessment ↗

• Uses relative binding free energy (FEP-type alchemical) calculations to compare warhead-bearing covalent inhibitors across two related cysteine proteases.
• Cruzain, the key protease of Trypanosoma cruzi (Chagas disease), and human cathepsin L, its close homolog, are modeled in parallel.
• Comparison highlights selectivity for the parasitic target versus off-target reactivity with the human enzyme, guiding optimization.

Assessment of the Binding Affinity of Covalent Inhibitors of Cruzain and Cathepsin L Using Relative Binding Free Energy ↗

• A new series of neutral, heterocyclic-linker-containing transthyretin (TTR) stabilizers is designed for improved brain and cerebrospinal fluid (CSF) penetration.
• Aims to address CNS/leptomeningeal manifestations of hereditary ATTR amyloidosis, where existing acidic stabilizers such as tafamidis show limited CNS exposure.
• Heterocyclic linker modifications reduced compound acidity relative to earlier chemotypes while reportedly preserving TTR tetramer-stabilizing potency and selectivity in vitro.

Discovery of Neutral and Cerebrospinal Fluid Penetrant Transthyretin (TTR) Stabilizers with Heterocyclic Linkers ↗

• A direct-to-biology (D2B) platform synthesizes candidate compounds at small scale and evaluates the crude reaction mixtures directly in biological assays, bypassing conventional purification.
• The approach couples miniaturized, automation-compatible chemistry with rapid biological readout to shorten the design-make-test cycle typical of early hit-finding and library exploration.
• Positioned within a broader wave of D2B methodology in medicinal chemistry, applicable to accelerating hit identification across diverse chemotypes.

Direct-To-Biology Platform Enabled Drug Discovery ↗

• Perspective-style article proposing that pharmacological inhibition of the epigenetic enzyme LSD1 (KDM1A) can modulate cellular sensitivity to nucleoside analogue therapeutics.
• Synthesizes evidence across myeloid malignancies and viral infections, two disease areas where nucleoside analogues are already established treatments.
• Argues LSD1-driven chromatin and transcriptional changes may underlie altered drug response, positioning LSD1 inhibitors as potential combination partners to enhance nucleoside analogue efficacy across both fields.

Targeting LSD1 Modulates Therapeutic Responses to Nucleoside Analogues: From Myeloid Malignancies to Viral Infections ↗

• Iron-binding chemistry anchors a new bacteria-targeted imaging probe engaging MurB, an enzyme unique to bacterial peptidoglycan (cell-wall) biosynthesis, for radiolabeling.
• The probe is proposed as a platform for PET (positron emission tomography), aiming to visualize actual bacterial infection sites in vivo rather than relying on nonspecific inflammation markers.
• By targeting a pathway absent in human cells, the approach could help clinicians distinguish genuine bacterial infection from sterile inflammation, addressing a longstanding gap in infectious-disease imaging.

Leveraging the Iron-Probe-MurB Interaction: An Enhanced Platform for PET Imaging of Bacterial Infections ↗

• Poly(disulfide)s are dynamic-covalent polymers whose guanidinium-rich chains cross cell membranes via thiol-mediated uptake, engaging surface thiols rather than classical endocytosis.
• This study probes the chemical basis of that uptake, linking polymer structure and disulfide exchange to membrane translocation and cytosolic release.
• It reinforces poly(disulfide)s as a macromolecular delivery modality for proteins, antibodies, and nucleic acids, bypassing lysosomal degradation.

The Nature of Cell‐Penetrating Poly(disulfide)s ↗

• A two-step route builds covalent genetically-encoded macrocycle libraries (cGELs): cysteines form the macrocycle via a diketone linchpin, then a separate Knorr-pyrazole step adds the electrophilic warhead.
• Separating cyclization (basic pH) from warhead installation (acidic pH) avoids the regioisomer mixtures that limited earlier one-pot chemical modification methods.
• This lets more diverse, reactive electrophiles be used safely, broadening covalent chemotypes accessible for selections against protein targets in DEL-style screens.

A Two-Step Synthesis of Covalent Genetically Encoded Libraries of Peptide-Derived Macrocycles Enables the Use of Electrophiles with Diverse Reactivity ↗

• A new series of fluorinated 4-methylideneisoxazolidin-5-one derivatives adds fluorine substituents onto the exocyclic methylidene-lactone-type isoxazolidinone core.
• The fluorinated analogs showed antiproliferative activity against cancer cell lines, with the reported cell-death mechanism attributed to induction of apoptosis.
• Structure-activity comparisons across the fluorinated series highlighted substitution patterns linked to improved potency and selectivity relative to non-fluorinated parent compounds.

Fluorinated 4-Methylideneisoxazolidin-5-ones: Synthesis and Apoptosis-Inducing Antiproliferative Activity ↗

• Imidazolium amino acids are proposed as cationic bioisosteres mimicking the size and charge of trimethyllysine, dimethylarginine, and arginine side chains.
• Binding to methyl-lysine reader domains is evaluated to see how closely the surrogates reproduce native residue recognition and selectivity.
• Cell assays indicate the charged isosteres can still traverse membranes, and SAR trends tie ring substitution to the affinity-permeability tradeoff for reader ligands and CPPs.

Evaluation of Binding and Cell Penetration of Imidazolium Amino Acids as Novel Bioisosteres for Trimethyllysine, Dimethylarginine, and Arginine ↗

• Researchers built a live-cell NanoBRET assay to test whether reported p53 Y220C ligands truly engage the mutant protein inside intact cells.
• The BRET-based readout gives a cell-based engagement ranking for known Y220C stabilizer/reactivator compounds, complementing prior biochemical binding data.
• Such cellular validation checks permeability and intracellular target occupancy, a key hit-to-lead checkpoint for this hard-to-drug p53 cavity mutant.

NanoBRET Target Engagement Enables Validation of p53 Y220C Ligands in a Cellular Context ↗

• Researchers used structure-guided design to develop a covalent small-molecule inhibitor of human butyrylcholinesterase (BChE), an enzyme increasingly implicated in Alzheimer's disease progression.
• The lead compound was engineered for blood-brain barrier penetration, a key hurdle for centrally acting cholinesterase inhibitors.
• In vivo testing showed procognitive efficacy, supporting covalent BChE inhibition as a potential treatment approach for Alzheimer's disease.

Structure-Guided Design of a Brain-Penetrant Covalent Inhibitor of Human Butyrylcholinesterase with In Vivo Procognitive Efficacy ↗

• Medicinal chemists designed single small molecules combining PARP inhibition with GPX4 inhibition, pairing DNA-repair blockade with ferroptosis induction in one compound rather than as a drug combination.
• Structure-activity relationship work identified a new dual-acting chemotype optimized for potency against both targets.
• Lead compounds showed antitumor activity in triple-negative breast cancer models, supporting the dual-mechanism approach as a possible way to broaden PARP inhibitor efficacy.

Discovery of Dual PARP/GPX4 Inhibitors for the Treatment of Triple-Negative Breast Cancer ↗

• Exelixis researchers optimized an aminopyrazole hit series targeting PLK4, a kinase essential for centriole duplication, culminating in the advanced compound EXEL-1855.
• Structure-guided SAR and selectivity profiling addressed off-target kinase liabilities that had limited earlier aminopyrazole PLK4 inhibitors such as centrinone.
• In preclinical tumor models, EXEL-1855 showed strong antitumor activity, supporting its selection as a development candidate.

Lead Optimization of an Aminopyrazole Scaffold to EXEL-1855, a Highly Selective PLK4 Inhibitor with Potent Antitumor Efficacy ↗

• Researchers built ionizable lipid nanoparticles with fluorinated lipid tails to encapsulate and deliver a PROTAC degrader payload.
• Tuning the degree of fluorination altered nanoparticle physicochemical properties and redirected intracellular trafficking, promoting more efficient endosomal escape into the cytosol.
• Optimized fluorinated formulations achieved greater cytosolic PROTAC release and stronger target-protein degradation than non-fluorinated lipid controls.

Fluorination-Tuned Ionizable Lipids Regulate Nano-PROTAC Trafficking for Enhanced Targeted Protein Degradation ↗

• Chemists built fluorinated Tn-antigen mimics using a tyrosine-linked GalNAc (Tyr-GalNAc) instead of the natural serine/threonine attachment, then conjugated them to bacteriophage Qβ virus-like particles.
• Qβ is a multivalent carrier platform known for driving strong antibody responses to small carbohydrate tumor antigens.
• The fluorinated Tyr-GalNAc-Qβ conjugates showed potent antitumor activity in preclinical models, adding to evidence that targeted fluorination can boost carbohydrate-antigen vaccine immunogenicity.

Synthesis of Fluorinated Tyr-GalNAc Antigens and Potent Antitumor Activity of Their Bacteriophage Qβ Conjugates ↗

• A new PROTAC degrader targets STAT6, the transcription factor that carries IL-4/IL-13 signals driving Th2-type allergic inflammation.
• Instead of inhibiting STAT6, the molecule links a STAT6-binding fragment to a degradation handle for potency and selectivity over related STAT proteins.
• It reportedly showed oral efficacy in preclinical models, pointing to a pill-based alternative to injectable biologics for atopic dermatitis.

Discovery of a Potent, Selective, and Orally Efficacious STAT6 PROTAC for the Treatment of Atopic Dermatitis ↗

• A new bioRxiv preprint investigates how the chemical architecture of antibody-oligonucleotide conjugates (AOCs) affects their performance as siRNA delivery vehicles.
• The work examines design variables such as linker composition, conjugation site on the antibody, and siRNA chemical modification pattern.
• Findings aim to clarify which structural choices most influence knockdown potency and delivery efficiency, informing rational AOC design.

Enhancing the efficacy of siRNA Antibody Oligonucleotide Conjugates (AOCs) through chemical design ↗

• Alliin, a natural cysteine-sulfoxide that chelates BACE-1's catalytic dyad, has poor pharmacokinetics, limiting its use as a drug lead.
• Researchers used a fragment-growing strategy guided by molecular dynamics simulations to build out from this core, aiming to improve affinity and drug-like properties.
• The campaign remains an early-stage computational effort, not a validated clinical candidate.

Optimizing Affinity and Pharmacokinetics of a Cysteine-sulfoxide Derivative as Potential Inhibitor of BACE-1 using Fragment Growing and Molecular Dynamics ↗

• Scientists converted an F2Pmp-based dual PTP1B/TCPTP inhibitor into a CRBN-recruiting bifunctional degrader, named X1.
• X1 shows improved potency, selectivity, and plasma exposure after intraperitoneal dosing versus earlier tools.
• Degrading both phosphatases boosts TCR signaling in T cells and IFNγ-driven JAK/STAT1 signaling in tumor cells, raising MHC-I antigen presentation.
• In a mouse tumor model, X1 alone or with anti-PD-1 increased T cell infiltration/activation and drove robust anti-tumor efficacy.

Discovery and Characterization of a Cereblon-Based Degrader for PTP1B and TCPTP ↗

• An earlier pyrazole-based CDK2 inhibitor scaffold was computationally redesigned around an imidazole core to improve selectivity over CDK1.
• The new chemotype was optimized simultaneously for potency, CDK1/CDK2 selectivity, and physicochemical properties.
• This work yielded INCB127443, an orally bioavailable candidate with favorable CDK1 selectivity and a flat pharmacokinetic profile enabling sustained in vivo target coverage.

Discovery of INCB127443: A Potent and Orally Available Inhibitor of Cyclin-Dependent Kinase 2 ↗

• SHP2 is a cytosolic protein tyrosine phosphatase implicated in oncogenic RTK and immune checkpoint signaling, making it a closely watched cancer/immuno-oncology target.
• Earlier allosteric SHP2 inhibitors have reached clinical trials but can face resistance mutations or PK limitations, motivating further chemotype exploration.
• This preprint reports a new series of N-aryl-1H-azaindole-derived allosteric SHP2 inhibitors, shifting away from orthosteric (active-site) inhibition approaches.

Switching from orthosteric to allosteric inhibition: Discovery of N-aryl-1H-azaindole-derived allosteric SHP2 inhibitors ↗

• Two-step triazole stapling built a peptide from DN-9's opioid segment, then added an NPFF pharmacophore via chimeric conjugation to form a multitarget agonist.
• The opioid-only stapled peptide acts as a μ-opioid agonist with partial δ-opioid activity; the conjugate targets μ-, κ-opioid and NPFF receptors with G-protein-biased μ signaling.
• Subcutaneous dosing of both compounds produced sustained, dose-dependent analgesia in acute and visceral pain models.

Two-Step Design of Triazole-Stapled Opioid Agonists Exhibiting Potent and Prolonged Peripheral Analgesic Activity ↗

• TrmD, a SPOUT-family bacterial tRNA methyltransferase without a human counterpart, is highlighted as a validated antibacterial target amid rising antimicrobial resistance.
• The review catalogs strategies used to discover small-molecule TrmD inhibitors—fragment-based design, high-throughput and virtual screening, click-chemistry-enabled direct-to-biology methods, molecular hybridization, and prodrug approaches.
• It synthesizes structural features and structure-activity relationships across these diverse chemical scaffolds to inform future inhibitor optimization.

TrmD: A Promising Antibacterial Target and Its Small-Molecule Inhibitors ↗

• Building on the TRPM7 blocker NS8593, researchers created a set of 2-aminobenzimidazole analogues and identified two standout leads, SDUY212 and SDUY225, validated by electrophysiological recordings.
• Both compounds slowed growth, migration and invasion in MCF-7 and MDA-MB-231 breast cancer cells and triggered apoptosis and cell-cycle arrest; SDUY212 also shrank tumors in xenograft-bearing mice.
• The anti-invasive effect appeared linked to reduced EGF-triggered STAT3 activation downstream of TRPM7.

Design, Synthesis and Biological Evaluation of New TRPM7 Channel Inhibitors as Potential Therapeutics for Breast Cancer ↗

• Research highlight on a stereoselective, cysteine-reactive molecule that locks the pro-apoptotic protein BAX into an inactive shape, blocking programmed cell death.
• Optimization yielded a lead compound suitable for in vivo dosing that limited liver-cell death and preserved organ function in a mouse model of acute liver injury.
• It also protected stem-cell-derived motor neurons from healthy and ALS-patient donors, pointing to wider relevance in neurodegenerative disease.

Covalent BAX inhibitor confers cytoprotection ↗

• Applies a hotspot-centric computational design strategy, grafting key antibody-binding side chains onto small L-peptide scaffolds that mimic how neutralizing antibodies engage influenza hemagglutinin.
• Draws design cues from the antigen-binding interfaces of broadly neutralizing antibodies FI6v3 and CR9114, both directed at the hemagglutinin stem.
• Aims to yield peptides that block the hemagglutinin conformational change driving membrane fusion, offering a structure-guided route to antibody-inspired flu therapeutics.

Antibody Hotspot-Centric de Novo Design of Peptide Inhibitors of Influenza A Virus Membrane Fusion ↗

• Reports a new series of caspase-1-targeting small molecules built on a dihydropyridine scaffold, a heterocyclic chemotype more commonly associated with calcium-channel drugs.
• Characterizes inhibitory activity with in vitro fluorescence-based enzymatic assays and extends the work into cell-imaging studies of caspase-1 activity.
• Positions the compounds as early leads given caspase-1's central role in inflammasome-driven inflammatory signaling.

Potent Caspase-1 Antagonists From Dihydropyridine Derivatives: In Vitro Fluorescence Assays and Cell Imaging ↗

• Starts from known capsid assembly modulator NVR 3-778 and applies a multi-objective optimization workflow combining structure-based fragment growing with medicinal chemistry.
• Machine-learning models are used alongside traditional design to jointly predict antiviral activity and drug-like/ADMET properties.
• The workflow generated and evaluated roughly four dozen novel sulfamoylbenzamide analogs.
• Lead compound 11B-6 emerged with superior antiviral potency and improved drug-like properties versus the starting scaffold.

Integrated AI-Driven Multi-Objective Optimization of Sulfamoylbenzamide-Based HBV Capsid Assembly Modulators: Discovery of 11B-6 with Superior Potency and Drug-like Properties ↗

• Second-generation analogs of the first-in-class caPCNA-selective inhibitor AOH1996, built by systematically modifying each of its four pharmacophoric regions.
• Explored substituent changes, bioisosteric swaps, linker adjustments, and scaffold hopping to improve on the parent compound.
• Lead analogs showed markedly improved cancer cell potency and better liver microsomal metabolic stability than AOH1996.
• Compounds were profiled across multiple cancer cell lines, including neuroblastoma and breast/colorectal cancer models.

Second-Generation AOH1996 Analogues with Enhanced Pharmacological Properties for Targeting PCNA ↗

• Targets CK1δ, an upstream kinase that stabilizes oncogenic NRAS mutant protein, as an indirect strategy against NRAS-driven melanoma.
• Reports discovery of compound 8u, a selective small-molecule degrader rather than a simple catalytic inhibitor.
• The degrader approach achieves high selectivity for CK1δ over closely related CK1 isoforms, addressing a limitation of earlier inhibitors.
• Treatment destabilizes mutant NRAS protein and suppresses oncogenic signaling in melanoma models.

Discovery and Synthesis of Selective Casein Kinase 1δ Degraders for Suppressing Oncogenic NRAS-Mutant Melanoma ↗

• Builds on a prior azaindole-quinazoline lead compound and addresses its limited blood-brain barrier penetration.
• Uses an intramolecular cyclization strategy to mask a hydrogen-bond-donating amine group that was prone to P-glycoprotein-mediated efflux.
• Resulting analogs retain strong DYRK1A inhibitory activity while markedly improving brain exposure.
• Optimized compounds reduce microglia-driven neuroinflammatory markers in disease-relevant models.

Brain Penetration Optimization and Anti-neuroinflammation Evaluation of Potent 6-Methyl-7-azaindol-3-yl-quinazoline DYRK1A Inhibitors for Alzheimer's Disease ↗

• A conspectus recounting a research program to design small-molecule inhibitors of human pancreatic α-amylase, key to starch digestion and post-meal glucose spikes.
• Frames the work against the rising global burden of type 2 diabetes and its glycemic complications.
• Traces iterative structure-based design that pushed inhibitor affinity from nanomolar into the picomolar range.
• Discusses translational potential of these ultra-potent inhibitors for managing postprandial hyperglycemia.

Discovery, Design, and Evaluation of Nanomolar to Picomolar Inhibitors of Human Pancreatic α-Amylase for Control of Postprandial Blood Glucose Levels ↗

• A new series of dihydropyridine-derived small molecules is reported as antagonists of caspase-1, a cysteine protease central to inflammasome signaling.
• Caspase-1 activation drives maturation of the pro-inflammatory cytokines IL-1β and IL-18, making it a longstanding target in inflammation and inflammasome-related disease research.
• The dihydropyridine scaffold, more commonly associated with calcium-channel pharmacology, is explored here as a chemotype for caspase-1 antagonism.
• Compound activity was characterized using in vitro fluorescence-based enzymatic assays to gauge caspase-1 antagonism.
• Cell imaging was used alongside the biochemical assays to examine compound behavior and target engagement in a cellular context.
• The study, published in ChemMedChem, presents this dihydropyridine series as a structure-activity starting point for further caspase-1/inflammasome-directed medicinal chemistry.

Potent Caspase-1 Antagonists From Dihydropyridine Derivatives: In Vitro Fluorescence Assays and Cell Imaging ↗

• PCNA supports at least 11 cellular pathways in DNA replication and repair; tumor cells express a distinct acidic isoform (caPCNA) not found in normal cells, creating a potential cancer-selective drug target.
• AOH1996 is City of Hope's first-in-class small-molecule PCNA inhibitor, which binds the PIP-box pocket to disrupt caPCNA protein interactions and selectively kill malignant cells.
• This paper describes second-generation AOH1996 analogues built through systematic structure-activity relationship work (substituent changes, bioisosteric replacement, linker and heteroatom modification, scaffold hopping) across all four pharmacophore regions.
• Lead analogues showed improved cellular potency against multiple cancer cell lines and better liver microsomal stability than first-generation AOH1996, supporting further lead optimization of this PCNA-targeted chemotype.

Second-Generation AOH1996 Analogues with Enhanced Pharmacological Properties for Targeting PCNA ↗

• Building on prior work identifying CK1δ as an upstream stabilizer of oncogenic NRAS, the team developed small-molecule degraders that trigger CK1δ's proteasomal breakdown.
• Chemical optimization focused on achieving selectivity for CK1δ over its close paralogs CK1α and CK1ε, which share highly similar kinase domains.
• Iterative structure-activity relationship analysis across a synthesized compound series balanced degradation potency, isoform selectivity, and cellular activity.
• Degrading CK1δ removed its support for oncogenic NRAS protein stability, lowering NRAS levels and dampening downstream signaling in melanoma cells.
• In NRAS-mutant melanoma cell models, the optimized degraders suppressed proliferation, positioning CK1δ degradation as a potential strategy for an otherwise hard-to-drug oncogenic driver.

Discovery and Synthesis of Selective Casein Kinase 1δ Degraders for Suppressing Oncogenic NRAS-Mutant Melanoma ↗

• Rhinitis is a heterogeneous upper-airway inflammatory condition whose chronic symptoms, especially in mixed and nonallergic disease, often resist first-line intranasal antihistamines and corticosteroids.
• The authors designed bifunctional small molecules combining muscarinic M3 antagonism, which limits glandular hypersecretion and rhinorrhea, with histamine H1 antagonism, which limits itch, sneezing and vasodilation.
• A structure-activity relationship campaign balanced potency at both receptors within a single scaffold while extending duration of action, targeting once-daily control rather than short-acting relief.
• Lead compounds were profiled for pharmacokinetics, receptor selectivity and safety, distinguishing this dual-target strategy from conventional single-mechanism antihistamines or anticholinergics.
• This positions combined M3/H1 antagonism as a candidate approach for rhinitis, including mixed and nonallergic forms, poorly controlled by existing monotherapies.

Discovery of Long-Acting Bifunctional Compounds with Muscarinic M3 and Histamine H1 Receptor Antagonism for the Treatment of Rhinitis ↗

• Researchers designed a new class of small molecules built on a benzothieno[3,2-d]pyrimidin-4(1H)-one scaffold that simultaneously inhibits PARP-1 and casein kinase 2 alpha (CK2α).
• PARP-1 inhibitors typically benefit only tumors with homologous recombination deficiency (HRD); pairing PARP-1 blockade with CK2α inhibition, a kinase linked to DNA damage response and cell survival signaling, is proposed to extend efficacy to HRD-proficient tumors and limit metastatic spread.
• Structure-activity relationship exploration identified substituents on the tricyclic core that support potent, balanced binding at both targets.
• In cellular and tumor models, the dual inhibitors reportedly show antiproliferative and anti-metastatic activity independent of HRD status, supporting dual-target inhibition as a route beyond BRCA-mutant-restricted use.

Simultaneous Inhibition of PARP-1 and CK2α by Novel Benzothieno[3,2-d]pyrimidin-4(1H)-one Derivatives: A Promising Strategy to Combat Homologous Recombination Deficiency-Independent Tumors and Metastasis ↗

• Hydroxamic acid-based HDAC inhibitors are limited by poor selectivity among metalloenzymes and by genotoxicity risk linked to isocyanate metabolites.
• The study applies a previously reported iron(II)-activatable conjugate platform to cage the pan-HDAC inhibitor panobinostat, aiming for tumor-conditional payload release.
• In multiple myeloma cell line models, the conjugate successfully caged HDAC inhibitory activity, and a bioisosteric control conjugate showed reduced genotoxicity relative to the free hydroxamate.
• Follow-up investigation identified the carboxylesterase CES1 as responsible for unexpected proteolytic instability of the panobinostat conjugate observed both in vitro and in vivo.
• The finding is noted as a focus for future work toward mitigating hydroxamate-associated toxicity and mutagenicity through more robust tumor-conditional activation.

Toward Tumor-Conditional Release of Histone Deacetylase Inhibitors from Nongenotoxic Drug Conjugates ↗

• Researchers developed Hsc70-Mediated Targeting Chimeras (Hsc70TACs), bifunctional small molecules that link an Hsc70-binding ligand to a ligand for a protein of interest, directing target degradation through chaperone-mediated autophagy rather than the ubiquitin-proteasome pathway used by PROTACs.
• The approach is proposed to extend the range of degradable targets, including certain cytosolic and cell-membrane proteins, and to offer an alternative route that may help address resistance risks associated with proteasome-dependent degraders.
• Degradation activity was demonstrated across multiple protein classes, including the transcriptional regulator BRD4, the regulatory protein MDM2, and the cell-membrane immune checkpoint protein PD-L1, across diverse cellular contexts.
• A lead BRD4-directed compound, B-2, showed favorable pharmacokinetic behavior and produced robust BRD4 degradation in vivo, supporting continued development of the Hsc70TAC modality.

Hsc70-Mediated Targeting Chimeras for Targeted Protein Degradation via Chaperone-Mediated Autophagy ↗

• NaV1.8 inhibition is a clinically validated non-opioid strategy for pain, with the marketed drug VX-548 (Journavx) serving as the benchmark; its metabolic pathways in humans and rats are well characterized.
• Researchers designed a new chemotype, 2-(2-benzimidazole)-substituted tetrahydrofurans, and applied structure-based optimization to circumvent VX-548's known metabolic liabilities while retaining nanomolar NaV1.8 potency and subtype selectivity.
• The resulting lead, compound 31, showed favorable oral bioavailability in rats, with plasma AUC more than 10-fold higher than VX-548, alongside potent in vivo analgesic efficacy.
• Pharmacokinetic behavior was consistent across species, with favorable profiles also seen in beagle dogs and cynomolgus monkeys.
• Compound 31 exhibited a favorable early safety profile, including no genotoxicity and weak hERG inhibition, supporting its status as a metabolically optimized preclinical lead for further evaluation.

Discovery of Novel 2-(2-Benzimidazole)-Substituted Tetrahydrofurans as Potent and Selective NaV1.8 Inhibitors for the Treatment of Pain ↗

• Approved PI3Kα inhibitors for HR+/HER2− PIK3CA-mutated breast cancer cause dose-limiting hyperglycemia and other adverse effects linked to inhibition of wild-type PI3Kα.
• Researchers designed a series of tetrasubstituted quinazolin-4(3H)-one compounds intended to selectively inhibit the oncogenic PI3Kα H1047R mutant.
• Selectivity for the mutant enzyme over wild-type PI3Kα is proposed to stem from a slow-on, slow-off binding mechanism.
• Lead compound 34 showed potent, mutant-selective activity in vitro along with a favorable ADME profile.
• In a T47D xenograft mouse model, compound 34 produced significant tumor growth inhibition without affecting blood glucose or serum insulin levels, unlike a benchmark approved PI3Kα inhibitor.
• The authors note that further optimization of compound 34 is needed to lower the efficacious dose and improve tolerability.

Discovery of Tetrasubstituted Quinazolin-4(3H)-ones as Wild-type-sparing, Highly Selective PI3Kα H1047R Inhibitors ↗

• Researchers built a combined screening pipeline pairing covalent fragment screening with a ligand-first design strategy to find chemical matter that reacts with lysine side chains rather than the more commonly targeted cysteines.
• The work focuses on the allosteric "latch" region of SHP2 phosphatase, a regulatory site distinct from the enzyme's catalytic pocket and from previously drugged allosteric tunnel sites.
• Computational modeling and experimental characterization were used together to guide fragment selection and to understand how covalent attachment at latch-site lysines affects the protein's conformational behavior.
• The approach yielded inhibitors described as the first potent, cell-active covalent compounds acting through this latch site, indicating the pocket can support functional, drug-like engagement rather than only structural characterization.
• The findings position lysine-directed covalent chemistry as a viable route for allosteric SHP2 modulation and provide a starting chemotype and site for further medicinal chemistry optimization.

Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2 ↗

• Researchers designed VHL-recruiting PROTAC degraders targeting EGFR, aiming to overcome acquired resistance to conventional EGFR kinase inhibitors in non-small cell lung cancer (NSCLC).
• Lead compounds C4 and D4 achieved potent, selective, and durable degradation of the EGFR Del19 and L858R resistance mutants.
• C4 induced cell cycle arrest and apoptosis, showed subnanomolar antiproliferative activity, and produced significant tumor regression in an HCC827 xenograft model at low intravenous doses on a reduced twice-weekly schedule.
• D4 was orally bioavailable and blood-brain barrier penetrant, and oral dosing completely halted tumor growth in vivo.
• The findings support a degradation-based strategy, rather than conventional inhibition, as a route to next-generation EGFR-directed therapies with potential central nervous system relevance.

Discovery of Potent and Selective VHL-Recruiting PROTAC Degraders Targeting EGFR with Improved Developability and Potent Anti-NSCLC Efficacy ↗

• Five new natural products, hyreptaones A-E (1-5), were isolated from the plant Hypericum reptans, defining a novel class of 1,2-seco-bicyclic polyprenylated acylphloroglucinols (BPAPs).
• Compounds 1-3 are the first 1,2-seco-BPAPs shown to derive from rare 3,3-diisoprenylated BPAP precursors, while 4 and 5 feature an unusual spirocyclic 6/5/5 ring system formed by further cyclization of the 1,2-seco-BPAP core.
• Structures were established using spectroscopic analysis together with X-ray crystallography.
• All five compounds preferentially inhibited the Cav3.1 T-type calcium channel over other T-type channel subtypes, indicating isoform selectivity.
• Compounds 4 and 5 additionally showed state-dependent modulation of Cav3.1 gating, marking them as a new class of Cav3.1 allosteric modulators.

1,2-seco-Bicyclic Polyprenylated Acylphloroglucinols as Isoform Selective Inhibitors of T-Type Calcium Channels ↗

• Researchers built Ctx-ETAC, a degrader-antibody conjugate pairing the approved EGFR antibody cetuximab with an engineered PROTAC payload, attached via a bioorthogonal reaction at a defined, controlled ratio per antibody.
• Its PROTAC payload pairs an indomethacin-derived COX-2 ligand with a VHL-recruiting peptide via a cathepsin B-cleavable linker, releasing the degrader selectively inside EGFR-positive tumor cells and activated fibroblasts.
• Degrading COX-2 in both cell types substantially curtails extracellular vesicle secretion, severing a key tumor-stroma signaling channel and nudging fibroblasts toward a quiescent, less tumor-supportive state.
• In a lung cancer xenograft model, Ctx-ETAC outperformed cetuximab alone in restraining tumor growth without added systemic toxicity, supporting microenvironment-targeted degradation as a therapeutic strategy.

Receptor-Guided Targeted Protein Degradation Collapses Extracellular Vesicle-Driven Tumor-Stroma Crosstalk ↗

• More than 300 X-ray cocrystal structures spanning diverse kinase-inhibitor complexes were analyzed to catalog recurring non-covalent contact patterns.
• The study highlights a set of conserved Lys, Asp, and Glu residues near the ATP pocket, dubbed "Catalytic Cluster Residues" (CCRs), that support catalysis and frequently contact bound inhibitors.
• Across most inhibitor chemotypes, these polar residues form non-covalent interactions rather than covalent bonds, making them broadly relevant handles for ligand design.
• Side-chain orientation of the CCRs tracks with the kinase's active or inactive conformational state, linking binding geometry to structural dynamics.
• The authors argue this conformation-coupled behavior can guide rational, structure-based inhibitor design aimed at improving potency and tuning selectivity across the kinome.

A Structural Perspective on Non-covalent Targeting of Conserved Polar Residues in Protein Kinases ↗

• Omaveloxolone is an FDA-approved Nrf2-activating drug, originally approved for Friedreich's ataxia, now repurposed as a STING-targeting agent.
• It binds the base of STING's ligand-binding domain, destabilizing the protein's folded structure.
• This triggers K27-linked polyubiquitination of STING and its subsequent degradation by the proteasome — a "molecular crowbar" mechanism.
• Unlike classical PROTAC-style bifunctional degraders, omaveloxolone acts as a single small molecule, directly destabilizing STING rather than using a ligand-linker-E3-ligase construct.
• In aged mice, omaveloxolone treatment reduced STING-pathway-driven inflammation, a hallmark of age-related "inflammaging."

Omaveloxolone functions as a molecular crowbar-like degrader of STING to alleviate aging-related inflammation ↗

• HDAC4 and HDAC7 — two class IIa histone deacetylases with tissue-restricted expression — were recently identified as distinct transcriptional drivers of Th17 cell differentiation.
• Using the class IIa scaffold TMP269 as a starting point, researchers designed and synthesized a new series of HDAC4/7-targeted inhibitors.
• Structure-guided optimization of the metal-proximal and hydrophobic-binding regions yielded analogs with improved potency and greater isoform selectivity.
• Luciferase transcriptional assays, protein-binding studies, and docking analyses revealed distinct SAR patterns that separately govern selectivity for HDAC4 versus HDAC7.
• The resulting compounds offer selective chemical probes for dissecting HDAC4 and HDAC7 function in Th17 biology and a foundation for future therapies targeting Th17-driven inflammatory disease, including IBD.

Structure-Guided Development of Selective HDAC4 and HDAC7 Inhibitors That Modulate Th17 Cell Transcription ↗

• Aromatase (CYP19A1) catalyzes the final step converting androgens to estrogens, and its activity drives tumor proliferation in estrogen receptor-positive (ER+) breast cancer, making it a long-validated target for hormonal therapy.
• Existing steroidal and nonsteroidal aromatase inhibitors (AIs) are effective as first-line treatments but face limitations from acquired resistance and off-target/tolerability issues, motivating a search for new chemical starting points.
• Researchers applied bioisosteric replacement strategies to a flavonoid-derived scaffold, a plant-derived chemotype structurally distinct from current AI drug classes, to generate a series of novel candidate inhibitors.
• The substitutions were assessed computationally for how they might alter predicted binding within the CYP19A1 active site, alongside their effects on physicochemical and ADME-relevant properties.
• The overall goal is a lead series that suppresses estradiol biosynthesis while addressing some of the structural liabilities associated with existing AI chemotypes.

Bioisosteric Design of Novel Flavonoid-Derived Aromatase Inhibitors to Reduce Estradiol Biosynthesis in ER+ Breast Cancer ↗

• RIBOTACs (ribonuclease-targeting chimeras) are heterobifunctional small molecules that recruit an endogenous ribonuclease to degrade a chosen RNA, rather than inhibiting a protein directly.
• This study applies the approach to cMYC mRNA; cMYC is an oncogenic transcription factor long considered "undruggable" because no direct small-molecule inhibitors have reached clinical use.
• Researchers systematically varied the length and rigidity of the linker connecting the RNA-binding ligand to the ribonuclease-recruiting moiety.
• Linker geometry proved to be a key determinant of how efficiently the RIBOTAC promotes cMYC mRNA degradation.
• Optimized linkers translated into improved downstream modulation of cMYC protein levels in cell-based assays.
• The findings support linker engineering as a general design lever for RIBOTAC-based RNA-targeted therapeutics.

Linker Optimization of cMYC RIBOTAC for Efficient cMYC Modulation ↗

• CYP8B1 is a liver enzyme in the bile-acid synthesis pathway now being explored as a drug target for metabolic disorders such as nonalcoholic fatty liver disease and type 2 diabetes.
• The project started from compound 1, a CYP8B1 inhibitor identified by high-throughput screening, which broke down too quickly to be tested in live animals.
• Chemists used structure-based design and metabolite identification to learn how the molecule degraded, then ran DMPK-guided analog synthesis to explore structure-activity relationships.
• That work produced compound 9, a quinoline analog with markedly improved metabolic stability.
• In mice, compound 9 showed robust in vivo CYP8B1 inhibition, providing a validated lead for further optimization.

Structure-Based Drug Design of Quinoline CYP8B1 Inhibitors for the Potential Treatment of Metabolic Disease ↗

• HDAC4 and HDAC7 are class IIa histone deacetylases with limited tissue expression, making them attractive, more selective epigenetic drug targets than broadly expressed HDAC family members.
• Both enzymes help drive the transcriptional program behind Th17 cell differentiation, a pathway linked to inflammatory bowel disease and other Th17-associated inflammatory conditions.
• Chemists reworked the metal-binding and hydrophobic contact regions of TMP269, a known class IIa scaffold, to build a new series of HDAC4/7-directed analogs.
• Reporter-gene, binding, and docking studies uncovered distinct structural features that separately steer potency toward HDAC4 versus HDAC7.
• The work delivered isoform-selective, potent compounds usable as chemical probes to separately study HDAC4 and HDAC7 function, and as starting points for Th17-targeted therapeutics.

Structure-Guided Development of Selective HDAC4 and HDAC7 Inhibitors That Modulate Th17 Cell Transcription ↗

• Researchers led by Seidler and colleagues designed a small-molecule inhibitor of p38δ (p38 delta), a MAP kinase linked to cancer, and reported its binding mechanism in Angewandte Chemie International Edition.
• Structural analysis showed the inhibitor initially collided with a flexible loop lining the kinase's ATP-binding pocket, a clash that would normally be expected to weaken or block binding.
• Instead of being excluded, the inhibitor caused that loop to change conformation and fold around the molecule, producing an unusually tight, self-encapsulating fit within the remodeled pocket.
• The authors present this induced-fit, pocket-remodeling behavior as a previously undescribed route to kinase selectivity, distinct from conventional structure-based design, which treats the binding pocket as a fixed template the inhibitor must be shaped to match.
• The finding suggests that deliberately exploiting pocket flexibility, rather than avoiding steric clashes, could become a strategy for engineering selectivity in future kinase-targeted drug design.

Thinking Outside the Binding Site: A Self‐Encapsulating Kinase Inhibitor Remodels Its Pocket to Achieve Selectivity ↗

• Researchers applied dynamic combinatorial chemistry (DCC), a hit-finding method in which reversible chemical building blocks assemble and reassemble under target guidance, letting the biological target itself select its best-binding partners.
• A new platform uses short peptide nucleic acid (PNA) tags to template three-fragment combinations, generating a library of 125,000 possible trivalent assemblies screened against thrombin.
• Candidate complexes are isolated by size-exclusion filtration and identified by MALDI mass spectrometry, compressing an entire selection-and-readout cycle to under an hour.
• Thrombin favored combinations engaging its active site and both flanking exosites at once, and this trivalent binding mode underlies the exceptionally tight affinity.
• The winning assembly is a fully reversible inhibitor with sub-picomolar affinity, achieving near-stoichiometric inhibition of thrombin activity.

Discovery of a Reversible Sub‐Picomolar Thrombin Inhibitor Using DCC ↗

• TRIM24 is a dual-module epigenetic "reader" whose bromodomain binds acetylated histones and is an established cancer drug-discovery target, though its nonhistone binding partners have been poorly defined.
• Researchers installed genetically encoded photocrosslinkers, AzF and BzF, at residue L922 within the bromodomain's acetyllysine pocket, preserving histone binding while enabling UV-triggered covalent capture of interacting proteins.
• Quantitative proteomics identified the nonhistone proteins NPM1 (AzF-enriched) and CDK9 (BzF-enriched), plus candidates MAP4, RAN, and SND1.
• ChIP-seq showed TRIM24, CDK9, and NPM1 co-localize near transcription start sites of cancer-associated genes; KEGG analysis tied the hits to several signaling pathways.
• The approach shows photocrosslinking can extend reader-domain interactome mapping beyond histones, yielding new candidate leads for chemical-probe and target-discovery work on TRIM24.

Mapping the Nonhistone Interactome of the TRIM24 Bromodomain Using Genetically Encoded Complementary Photocrosslinkers ↗

• Cryo-EM structures of the CTLH-MKLN1 E3 ligase, bound to three distinct substrate proteins, map how this receptor engages its targets.
• MKLN1 uses its discoidin and Kelch domains together, contacting substrates at multiple points rather than one binding surface.
• MKLN1 recognizes copies of itself via discoidin-Kelch pairing between dimers, competing with binding of other substrates.
• For ZMYND19 and adaptor-bound UNG2, C-terminal arginine residues insert into MKLN1's Kelch channel, marking MKLN1 as an arginine/C-degron receptor.
• A separate adaptor positions UNG2's acetylated N-terminus in an internal tunnel, revealing a distinct acetyl-N-terminal degron pathway.
• The findings broaden known E3 ligase substrate-recognition mechanisms, relevant to targeted protein degradation strategies beyond CRBN and VHL.

Multimodal substrate recruitment enables CTLH-MKLN1 E3 ligase to target N-, C-, and internal degrons ↗

• BmTACs — a new class of brain-penetrant degrader molecules — fuse a macrocyclic peptide shuttle to a PROTAC-type small-molecule module.
• The peptide shuttle exploits a transcytosis route across brain blood vessels that becomes more active with age, enabling efficient blood-brain-barrier crossing and neuronal delivery.
• A chemical cage on the degrader's VHL-recruiting ligand keeps it silent until it meets the high-oxidative-stress conditions found in Alzheimer's-affected tissue, limiting activity elsewhere in the brain.
• Once activated, the compound selectively degrades an activated, disease-linked form of the kinase DAPK1.
• In aged Alzheimer's-model mice, systemic treatment reduced activated DAPK1, lessened amyloid-beta and tau pathology, and improved cognitive function, demonstrating an aging-adapted strategy for brain-targeted protein degradation.

Blood-Brain Barrier-Permeable Macrocyclic Chimeras (BmTACs) for Targeted Protein Degradation in the Aging Brain ↗

• Oligonucleotide backbone chemistry gets a new modular entry point: an H-phosphonate diester dinucleotide 'blockmer' platform that builds backbone-modified oligonucleotides through standard solid-phase synthesis.
• The method exploits the ambiphilic reactivity of H-phosphonate diesters, allowing diverse phosphate backbone modifications to be installed without air- or moisture-sensitive P(III) reagents or hazardous chemicals.
• Accessible backbone modifications span a wide range, from simple alkyl substitutions to sulfonamide-linked phosphate analogs, well beyond conventional phosphorothioate-type chemistries.
• Because the dinucleotide blockmers are compatible with existing solid-phase assembly workflows, they can be combined and positioned flexibly within a single oligonucleotide sequence.
• The platform is designed to enable systematic backbone structure-activity relationship studies in oligonucleotide drug discovery, providing a scalable and robust route for rapid analog generation.

Versatile H-Phosphonate Platform for Backbone-Modified Dinucleotide Blockmers Enabling Oligonucleotide SAR ↗

• A programmable, bifunctional pyridine scaffold bearing a thianthrenium leaving group and a fluorine handle enables two sequential, chemoselective coupling reactions — first with alkylamines, then with cysteine thiols.
• The resulting aryl-cysteine linkage is non-chiral and stable, addressing limitations of existing bioconjugation approaches that often yield reversible linkages or stereochemical mixtures.
• Both coupling steps show high functional-group tolerance and chemoselectivity, making the chemistry compatible with complex peptides and proteins.
• The platform was applied to late-stage peptide diversification and stapling, as well as site-selective protein functionalization.
• Researchers also used the method to build an analog of the HER2-targeting antibody-drug conjugate MRG002 with a tunable drug-to-antibody ratio, reporting improved payload retention in serum relative to conventional linkage chemistry.

Modular Assembly of Bioconjugates Enabled by a Pyridine-Based Chemoselective Sequential Conjugation Platform ↗

• Ligands that bind deubiquitinating enzymes (DUBs) without blocking their catalytic activity are notoriously hard to find — a new on-bead, proximity-driven functional screening platform is designed to identify them.
• Such noninhibitory DUB ligands are essential for building DUBTACs (deubiquitinase-targeting chimeras), bifunctional molecules that stabilize target proteins by recruiting DUBs to strip ubiquitin marks, the inverse of degrader-based targeted protein degradation.
• That rarity has made noninhibitory DUB ligands the central bottleneck in DUBTAC development.
• Using the platform, the team discovered a previously unreported noninhibitory ligand for the deubiquitinase USP7.
• Conjugating this USP7 ligand to a CFTR-binding moiety produced a DUBTAC lead, WJ045, which stabilized cellular CFTR protein levels.
• The results demonstrate the platform's utility for discovering DUB-recruiting ligands and advancing targeted protein stabilization, with relevance to cystic fibrosis biology.

A Proximity-Driven Functional Screening Platform for the Discovery of Noninhibitory USP7 Ligand Enabling Targeted Protein Stabilization ↗

• WBP4, a spliceosome-associated scaffold protein long considered undruggable, now has a first-in-class molecular glue degrader: dWBP4-1, which selectively eliminates it.
• The compound works through the CRBN E3 ligase, engaging WBP4 via a canonical G-loop interface to trigger rapid, highly potent degradation.
• Proteome-wide profiling showed the degrader was highly selective, with minimal off-target effects on gene expression or splicing patterns.
• The team pinpointed a compact 41-amino-acid region of WBP4 sufficient to serve as a degradation tag, naming the resulting chemical-genetic system "wTAG."
• When attached to other proteins of interest, wTAG enabled clean, dose-dependent degradation without the "hook effect" that limits many degrader tools, expanding its potential as a general research platform.

Selective and Potent First-in-Class CRBN-Dependent Molecular Glue Degraders of WW Domain-Binding Protein 4 ↗

• PA-HDCI, a near-infrared fluorogenic probe built on the HDCI fluorophore scaffold, localizes to the endoplasmic reticulum and reports on human carboxylesterase 2A (hCES2A) activity in living cells and animals.
• The probe combines a large Stokes shift, high metabolic stability, and reliable ER targeting, enabling in situ, real-time imaging of hCES2A function across multiple biological systems.
• Using PA-HDCI in a high-throughput screening assay, the team identified compound A4, a highly potent covalent inhibitor of hCES2A.
• hCES2A is the intestinal enzyme that converts the chemotherapy drug irinotecan into its toxic active metabolite, driving irinotecan-induced intestinal toxicity (IIT).
• In tumor-bearing mouse models, A4 showed a favorable safety profile and reduced irinotecan-associated intestinal toxicity while therapeutic efficacy was maintained.
• Together, the work delivers both a new imaging tool and a validated drug-discovery platform for hCES2A-targeted therapeutics.

An ER-Targeting Near-Infrared Fluorogenic Probe for In Situ hCES2A Functional Imaging and Inhibitor Discovery ↗

• Discovered dWBP4-1 through proteomic profiling of a CRBN-binding compound library, followed by SAR optimization.
• Acts as a molecular glue, forming a CRBN ternary complex via a canonical G-loop-mediated interaction to recruit WBP4 (WW domain-binding protein 4), a spliceosome-associated scaffold protein.
• Degradation is rapid and occurs at nanomolar concentrations.
• Selectivity across the proteome is reported as high, with minimal downstream transcriptomic or alternative-splicing effects observed elsewhere.
• Mapped a minimal ~41-residue WBP4 degron sequence and used it to build "wTAG," a fusion-tag degradation platform.
• wTAG enables monotonic, dose-dependent degradation without the hook effect seen in some bifunctional degraders.

Selective and Potent First-in-Class CRBN-Dependent Molecular Glue Degraders of WW Domain-Binding Protein 4 ↗

• Custom bifunctional amino acids — carrying a VHL-recruiting ligand and a variable linker — are incorporated directly during solid-phase peptide synthesis, an alternative to conventional PEG-based linkers for building cyclic peptide degraders.
• A SICLOPPS-derived cyclic peptide HIF-1 inhibitor serves as the warhead, yielding cyclic peptide PROTACs (CP-PROTACs) that engage VHL in a productive ternary complex.
• The degraders lower HIF-1α levels and hypoxia-response signaling across multiple cancer cell lines.
• Degradation is oxygen-state dependent — robust under moderate hypoxia but largely lost under more severe hypoxia, even though the degrader still engages and marks HIF-1α there.
• The activity loss reflects a kinetic mismatch, not a binding failure: HIF-1α resynthesis outpaces degradation, pointing to a general ceiling on PROTAC efficacy against rapidly replenished targets.

Cyclic Peptide PROTACs Restore VHL-Mediated HIF-1α Degradation in Hypoxia ↗

• Combined protein–ligand docking, ML force fields, quantum chemistry, and free-energy perturbation (FEP) to screen roughly 5 million hypothetical photoactive PARP1 ligands.
• Docking identified candidates with differential PARP1 binding between light-exposed and dark states; ML force fields and QM calculations predicted pKa, absorption spectra, and thermal half-lives, while graph-based surrogate models screened the remaining library.
• Excited-state nonadiabatic dynamics simulations (with ML force fields) estimated photoswitching quantum yields; FEP refined binding-affinity predictions for top hits.
• Prioritized a small set of synthetically accessible candidates combining red-shifted absorption (favoring deeper tissue penetration), therapeutically suitable thermal half-lives, and light/dark-selective PARP1 binding.
• Predictions were experimentally validated, demonstrating an end-to-end computational-to-experimental pipeline for designing light-activated (photopharmacological) cancer therapeutics.

Computational Design and Experimental Validation of Photoactive PARP1 Inhibitors ↗

• Introduces reactive metallo-scaffolds (r-mS), a new class of covalent metal complexes bearing a chloroacetamide electrophile designed to engage ligandable cysteines across the proteome.
• Chemoproteomic profiling of a focused r-mS series in HEK293T cell lysate mapped novel cysteine engagement proteome-wide.
• Metal identity, arene substituents, and overall scaffold topography together tune cysteine reactivity and targeting selectivity.
• Lead compound r-mS-2 engages a cysteine within the functionally relevant SAM-binding domain of the methyltransferase PRMT1, confirmed by intact-protein LC-MS.
• That engagement functionally inhibits PRMT1 activity, tying a covalent hit directly to modulation of a validated target.
• Positions the platform as a generalizable route to target discovery for rational, next-generation metallodrug design.

Proteome-Wide Target Identification Using Reactive Metallo-Scaffolds (r-mS): A Platform for Metallodrug Discovery ↗

• A PNA-templated dynamic combinatorial chemistry (DCC) platform assembles a three-fragment library (~125,000 possible combinations) using DNA/PNA hybridization handles for unbiased equilibration.
• Thrombin itself templates the library, selecting and amplifying the best-binding fragment combination; size-exclusion filtration coupled with MALDI mass spectrometry gives a full selection-to-readout cycle in under an hour.
• The selected trivalent assembly engages thrombin's active site plus both exosites simultaneously, driving exceptionally high (sub-picomolar-range) binding affinity and near-stoichiometric inhibition.
• Unlike covalent thrombin inhibitors, binding is fully reversible — pharmacologically relevant for an anticoagulant, where reversibility matters for managing bleeding risk.
• Demonstrates target-templated DCC as a rapid route to multivalent, exosite-spanning inhibitors, even against a well-studied target.

Discovery of a Reversible Sub-Picomolar Thrombin Inhibitor Using DCC ↗

• Genetic code expansion installed site-specific photocrosslinkers (AzF and BzF) at residue L922, within the acetyllysine-binding pocket of the TRIM24 bromodomain.
• Both crosslinker variants retained recognition of acetylated histones and crosslinked efficiently under UV, enabling interaction-based protein profiling (IBPP) in a native context.
• Quantitative proteomics of the two complementary probes gave differing capture profiles: AzF enriched for NPM1, BzF enriched for CDK9, with MAP4, RAN, and SND1 as additional candidates.
• ChIP-seq showed TRIM24, CDK9, and NPM1 co-occupying regions near transcription start sites of cancer-associated genes.
• Together the results suggest the TRIM24 bromodomain reads acetylation on nonhistone proteins as well as histones, broadening its reader function and informing chemical-probe design against this pocket.

Mapping the Nonhistone Interactome of the TRIM24 Bromodomain Using Genetically Encoded Complementary Photocrosslinkers ↗

• Researchers screened a library of 1,280 known bioactive compounds in search of pharmacological activators of the mitochondrial calcium uniporter complex (MCUc), a target for which potent, selective agonists have been scarce.
• The screen identified CGP7930 — a compound previously characterized as a GABA-B receptor allosteric modulator — as a potent activator of mitochondrial calcium uptake, highlighting a drug-repurposing angle for a difficult target.
• Mechanistic follow-up showed the activating effect depends on MICU1, a key regulatory subunit of the uniporter complex, pointing to a specific mode of action rather than a nonspecific membrane effect.
• Enhanced mitochondrial calcium entry translated into improved cardiac contractile bioenergetics, suggesting relevance to conditions involving impaired heart energy metabolism.
• The work provides a valuable pharmacological tool compound and a starting point for developing more selective next-generation MCU activators.

High-throughput screen identifies a potent MCU activator boosting cardiac contractile bioenergetics ↗

• Camptothecin-class payloads such as DXd currently dominate antibody-drug conjugate (ADC) design, powering approved drugs in the Enhertu family.
• Researchers created a new homocamptothecin analog, H2, built around a simplified seven-membered-ring (hydroxybutyl) core that avoids the lengthy, multi-step F-ring synthesis required for DXd-type payloads.
• H2 retained potent intrinsic cytotoxicity while showing markedly better resistance to hydrolytic breakdown than earlier homocamptothecin designs.
• Trastuzumab-based ADC candidates carrying H2 produced strong bystander-killing effects and antiproliferative activity in vitro, mirroring T-DXd.
• In a HER2-positive xenograft tumor model, the H2-based conjugates matched the antitumor efficacy of the benchmark payload T-DXd.
• The results position the simplified homocamptothecin scaffold as a promising, more synthetically accessible class of next-generation ADC payloads.

Homocamptothecin Payloads with Enhanced Potency for Antibody-Drug Conjugates ↗

• VAV1 is a hematopoietic-restricted signaling protein of interest in blood cancers and autoimmune conditions, prompting efforts to target it via induced protein degradation.
• High-throughput, unbiased global proteomics screening identified phenyl-glutarimide degrader compounds that recruit CRBN to selectively degrade VAV1.
• VAV1's C-terminal SH3-2 domain proved essential for ternary complex formation, and structural work uncovered a novel "RT-loop" degron there—distinct from the "G-loop" degrons used by other CRBN glues—validated by mutagenesis.
• An AI-based protein structure-prediction workflow modeled the ternary complex to support this mechanistic finding.
• Free energy perturbation calculations on the predicted structures generated cooperativity scores that correlated with experimental potency, demonstrating a computational strategy to prioritize and optimize molecular glue analogs faster than empirical screening alone.

Leveraging high-throughput proteomics and AI-based protein folding to accelerate VAV1 molecular glue discovery ↗

• B3GAT3 (beta-1,3-glucuronosyltransferase) is overexpressed in hepatocellular carcinoma (HCC) and correlates with poor patient prognosis, marking it as a promising but previously untargeted anti-cancer target.
• The research team started from TMLB-C16, an in-house lead compound with micromolar-range inhibitory potency against B3GAT3.
• Using structure-guided design, they synthesized 60 novel derivatives built on a 6-methoxyquinoline-4-carboxamide scaffold, systematically probing structure-activity relationships (SAR).
• This optimization campaign identified TMLB-G9, a candidate whose potency improved dramatically, moving from the micromolar starting point to nanomolar activity.
• TMLB-G9 is reported as a first-in-class B3GAT3 inhibitor, offering a new chemical starting point for potential HCC drug development.

Structure-Guided Design, Synthesis, and Evaluation of Novel 6-Methoxyquinoline-4-carboxamide Derivatives as First-in-Class Nano-Molar B3GAT3 Inhibitors for the Treatment of Hepatocellular Carcinoma ↗

• Starting from JK-4b, a potent but overly cytotoxic non-nucleoside reverse transcriptase inhibitor (NNRTI), researchers pursued structure-guided optimization to fix its safety liability.
• Design efforts targeted the NNRTI entrance channel, a sub-pocket near the classical allosteric site, to reshape how analogs bind reverse transcriptase and reduce off-target toxicity.
• Structure-activity relationship (SAR) studies across this new series pointed to compound 9n as the standout, with markedly improved selectivity and much lower cytotoxicity than JK-4b.
• Despite the safety redesign, 9n kept potent antiviral activity against both wild-type HIV-1 and clinically relevant drug-resistant variants, preserving the lead's core strength.
• The work illustrates entrance-channel-focused chemistry as a practical strategy for detoxifying promising but toxicity-limited NNRTI candidates.

Targeting the HIV-1 NNRTI Entrance Channel: Structure-Guided Optimization for Enhanced Safety and Selectivity ↗

• This J. Med. Chem. perspective synthesizes lessons from four clinical-stage oral, nonpeptidic GLP-1 receptor agonists—danuglipron, lotiglipron, DA-302168S, and orforglipron—to outline a design blueprint for next-generation candidates.
• It frames a broader modality shift in metabolic disease therapeutics: from injectable peptide GLP-1RAs toward oral small molecules that could improve dosing convenience and patient acceptance.
• Orforglipron is highlighted as the first oral small-molecule GLP-1RA to reach approval, marking a proof-of-concept milestone for the class.
• The authors distill recurring structure-activity relationship tradeoffs among these first-generation candidates—balancing receptor potency, tolerability, and oral bioavailability—that shaped each program's clinical trajectory.
• Based on these comparisons, the review proposes design principles intended to guide future medicinal chemistry efforts toward improved oral GLP-1RAs.

Oral Small-Molecule GLP-1 Receptor Agonists: Lessons from Clinical Candidates and a Blueprint for Next-Generation Design ↗

• This is a perspective/analysis article, not a new experimental study, focused on Plasmodium falciparum apical membrane antigen 1 (PfAMA1) as an anti-malarial drug target.
• PfAMA1 binds rhoptry neck protein 2 (PfRON2) to form the moving junction that enables the malaria parasite to invade red blood cells, making this protein-protein interaction a key therapeutic target.
• Most structure-based inhibitor design has targeted the hydrophobic trough, a well-defined groove on PfAMA1 that accommodates the PfRON2 peptide.
• The authors highlight a domain 2 (D2) loop near the trough that shows cryptic, conformation-dependent dynamics rather than a fixed structure.
• They argue this loop flexibility, previously overlooked, meaningfully shapes how PfAMA1 recognizes PfRON2.
• The perspective calls for future anti-malarial drug design to incorporate D2 loop dynamics alongside the trough itself, rather than treating the binding site as static.

Beyond the Hydrophobic Trough of PfAMA1: Pivotal Roles of Cryptic Loop Dynamics Inform Anti-Malarial Therapeutic Design ↗

• DNA-encoded libraries (DELs) let researchers screen ultralarge collections of macrocyclic peptides to find hit compounds for drug discovery, but efficient on-DNA cyclization chemistry has remained a bottleneck.
• A new on-DNA macrocyclization method uses sulfur(VI) fluoride exchange (SuFEx), a fast, click-type reaction, to close peptide rings directly on DNA tags.
• The design embeds a phenol and an aryl sulfonyl fluoride within a single DNA-tagged peptide, positioning the two groups to react with each other intramolecularly.
• Simply dissolving the construct in basic aqueous buffer triggers rapid, high-conversion cyclization without added catalysts or harsh conditions.
• The method enables efficient, high-yielding synthesis of ultralarge DNA-encoded macrocyclic peptide libraries, expanding the chemical space available for DEL-based hit discovery.

SuFEx Cyclization Enables DNA-Encoded Macrocyclic Peptide Libraries for Drug Discovery ↗

• CD38 is an enzyme central to NAD+ metabolism and calcium signaling in cells, and interest has grown in targeting it for neurological and psychiatric conditions.
• The authors designed a new tricyclic chemical series that binds CD38 by forming an adduct with the ADPR co-substrate, inhibiting the enzyme through an uncompetitive mechanism.
• Locking the molecules into their active shape — achieved by covalently linking a six-membered heteroaromatic core to an imidazole warhead — boosted biochemical activity against both mouse and human CD38.
• Iterative tuning of the core and linker chemistry, guided by physicochemical properties, improved how much unbound compound reached the brain relative to plasma in mice.
• The resulting lead, compound 16, raised NAD+ levels in mouse brain and lung tissue in a dose-dependent manner across an oral dosing range tested in vivo.

Design and Exploration of a Tricyclic Series of CNS-Penetrant CD38 Small Molecule Inhibitors ↗

• NatA catalyzes a large share of eukaryotic Nα-acetylation, a co-translational modification important for protein stability, localization and function; no validated small-molecule NatA probe had previously been reported.
• Screening an in-house ~700-compound library and optimizing a thiadiazolidinedione scaffold identified tideglusib (YD3139) — a clinical-stage GSK-3β inhibitor — as a hit, repurposing a known drug toward NatA.
• Mechanistic studies showed tideglusib first binds NatA allosterically, after which CoA released during catalysis chemically modifies it into a reversible covalent adduct, a previously undescribed catalysis-dependent inhibition mechanism.
• The compound showed low-micromolar potency against yeast and human NatA with good selectivity over other NAT family members, and proteomics confirmed on-target activity in yeast cells, validating it as a mechanistic chemical probe.

Tideglusib as a First-in-Class Chemical Probe for NatA: Identification, Mechanism, and Cellular Validation of an Allosteric, CoA-Dependent Inhibitor ↗

• Researchers combined XChem crystallographic fragment screening with in silico screening, then merged fragment hits into covalent leads targeting the Kalirin-Rac1 GEF-GTPase complex.
• Instead of directly competing with GTP/GDP for Rac1's binding site, the covalent compounds act as molecular glues, locking Kalirin and Rac1 into an inactive ternary complex that blocks nucleotide exchange.
• Two resulting inhibitors, RS-009 and MC-278, reduce Kalirin's GEF activity through this dual action: partial nucleotide competition plus stabilization of the non-productive complex.
• Biochemical selectivity panels and cellular activity-based protein profiling show the compounds can distinguish among different GEF-GTPase pairs rather than acting indiscriminately.
• The authors frame this as an alternative to direct GTPase inhibition that could offer finer spatiotemporal control, positioning RS-009/MC-278 as chemical probe candidates.

Discovery of a molecular glue inhibitor that stabilises a non-productive Kalirin-Rac1 complex ↗

• Chemists conjugated the beta-lactam antibiotic aztreonam to aerobactin, a bacterial iron-scavenging siderophore, exploiting bacteria's own iron-uptake machinery as a 'Trojan horse' to smuggle the drug inside cells.
• A modular synthetic route enabled controlled mono- and di-functionalization of aerobactin, with late-stage click-chemistry (CuAAC) attachment of payloads, providing a flexible platform applicable beyond this single conjugate.
• The lead monovalent conjugate was markedly more potent than aztreonam alone against a hypervirulent, clinically concerning Klebsiella pneumoniae strain, a substantial improvement over the parent antibiotic.
• Competition and iron-dependent activity studies confirmed delivery proceeds through the aerobactin iron-acquisition pathway, supporting genuine siderophore-mediated uptake rather than incidental potency gains.
• The results establish aerobactin as a viable scaffold for delivering antibacterial payloads against multidrug-resistant, hypervirulent Enterobacteriaceae.

Modular Synthesis of Aerobactin–Aztreonam Conjugates with Enhanced Activity against Hypervirulent Klebsiella pneumoniae ↗

• Researchers used bicyclic genetically encoded peptide libraries (BiGEL) — phage-displayed peptides chemically stapled into two rings — to search for inhibitors of Siglec-7, a glycan-binding immune receptor considered notoriously hard to target with small molecules.
• Sequencing-based panning against Siglec-7 nominated hundreds of candidate peptides; a subset were confirmed as genuine binders by surface plasmon resonance and as functional disruptors of the Siglec-7:GD3 interaction by competitive ELISA, with machine learning models identifying further hits of similar potency.
• Structure-activity work showed the bicyclic ring architecture itself is essential for potency, and NMR studies located one optimized lead's binding site away from the canonical glycan-binding domain, pointing to a possible allosteric mechanism.
• Cell-based multivalent binding assays confirmed engagement with Siglec-7 but also revealed considerable nonspecific binding to receptor-negative cells, highlighting a selectivity challenge still to be resolved.

Noncarbohydrate Inhibitors of Sialic Acid-Binding Immunomodulatory-Type Lectin-7 (Siglec-7) Discovered from Genetically Encoded Bicyclic Peptide Libraries ↗

• TRI-611 is an orally dosed molecular glue degrader designed to eliminate ALK fusion proteins that drive a subset of non-small cell lung cancers.
• Rather than blocking ALK's active site like conventional inhibitors, it recruits the E3 ligase adaptor cereblon to a distinct surface on ALK, forming a complex that tags the protein for degradation.
• The molecule is reported to be highly selective, sparing other cereblon-dependent targets and unrelated kinases, and it degrades both wild-type and kinase-inhibitor-resistant ALK fusion variants.
• A central finding is brain penetrance: TRI-611 produced tumor regressions in intracranial as well as subcutaneous models, addressing CNS metastases that limit many existing ALK-targeted therapies.
• Degradation was rapid and long-lasting, and combining TRI-611 with standard ALK inhibitors produced more durable responses in preclinical models.

TRI-611, a selective, brain-penetrant molecular glue degrader of ALK ↗

• The EP4 receptor (EP4R), a prostaglandin E2 receptor subtype, is a promising immuno-oncology target because its signaling dampens antitumor immunity and drives tumor-associated inflammation.
• A scaffold hopping strategy moved medicinal chemists away from earlier EP4R antagonist chemotypes to a novel chemical series with improved potency and pharmacokinetics.
• Structure-activity relationship (SAR) studies then guided lead optimization, balancing target potency, selectivity, and drug-like properties.
• This process yielded DT-9081, an orally bioavailable small-molecule EP4R antagonist combining potent receptor antagonism, favorable ADME properties, and a clean preclinical safety profile.
• In vitro and in vivo pharmacology data support DT-9081's ability to modulate tumor immunity, and the compound has already completed a Phase I monotherapy trial in patients with solid cancers.

Discovery of DT-9081, a Potent and Orally Bioavailable Small Molecule Antagonist of the EP4 Receptor for the Treatment of Solid Cancers ↗

• Rather than inhibiting or trapping the PARP1 enzyme like approved PARP inhibitors (PARPis), researchers targeted the PARP1 gene promoter itself to shut down PARP1 production at the transcriptional level, aiming to avoid the hematologic toxicity and resistance mechanisms associated with PARPi-mediated PARP1 trapping.
• The promoter region forms a non-canonical (3+1) hybrid G-quadruplex structure distinguished by an adenine bulge, a distinctive DNA fold not previously exploited as a drug target.
• Combining computational modeling with biophysical characterization, the team identified a small molecule that selectively engages this unusual G-quadruplex architecture.
• In multiple myeloma cells, the compound reduced PARP1 expression, disrupted downstream DNA repair signaling, and triggered DNA damage-associated apoptosis.
• Healthy blood cells were largely spared, pointing to a possible therapeutic window distinct from conventional PARP inhibitor toxicity profiles.

Hit It before It Starts: Targeting a (3 + 1) Hybrid Non-canonical G-Quadruplex to Silence PARP1 in Cancer ↗

• GRP78 (BiP/HSPA5) is a chaperone in the highly conserved HSP70 family, making isoform-selective inhibitors difficult to design.
• Using a Direct-to-Biology (D2B) strategy — synthesizing and screening compounds without intermediate purification — researchers identified compound 12 as a selective GRP78 inhibitor.
• Compound 12 binds the peptide-binding pocket in GRP78's substrate-binding domain and is selective for GRP78 over other tested HSP70 isoforms.
• It potently and selectively kills A549 lung cancer cells while showing minimal activity in other tested lung cancer cell lines.
• Cellular thermal shift assay (CETSA) confirmed cellular target engagement, and compound 12 modulates GRP78-linked unfolded protein response (UPR) stress signaling.
• The authors present compound 12 as a chemical probe for studying GRP78 biology and a starting point for GRP78-targeted therapeutics.

Development of Isoform-Selective GRP78 Inhibitors from a Direct-to-Biology Strategy ↗

• Researchers describe a "2-in-1" PROTAC design that merges the CRBN-recruiting ligand into the capping group of an HDAC8 warhead, rather than linking two separate ligands.
• This lets one structural motif engage both HDAC8 and the CRBN E3 ligase, unlike conventional heterobifunctional PROTACs, whose separate POI- and E3-binding units plus linker often yield large, poorly drug-like molecules.
• Relative to the team's earlier HDAC8 degrader YX862, the new compact degraders show improved selectivity, lower molecular weight, and better overall drug-like properties.
• The compounds also achieved effective HDAC8 degradation in vivo, indicating therapeutic potential beyond cell-based activity.
• The study proposes a broader design framework for building smaller, more efficient PROTACs by integrating target engagement and E3 ligase recruitment into a single motif.

A 2-in-1 Strategy for the Discovery of Compact HDAC8 Protac Degraders ↗

• p53 is the tumor suppressor most frequently inactivated in cancer, and hotspot mutations such as R280K and R273H destabilize the folded DNA-binding domain, making mutant p53 reactivation a long-standing 'undruggable' target class.
• The study describes RVJB59, a small molecule from a tryptophanol-derived oxazoloisoindolinone series, designed to covalently engage mutant p53 protein rather than bind it only reversibly.
• Biophysical thermal-stability assays reported for this compound series show increased melting stability of mutant p53 DNA-binding domains, consistent with partial restoration of a more folded, wild-type-like conformation.
• Combining covalent engagement with thermostabilization supports a mutant-reactivation strategy aimed at restoring p53 tumor-suppressor function in cancers driven by the R280K and R273H mutations.

Covalent Targeting and Thermostabilization of Oncogenic R280K and R273H Mutants p53 by Small Molecule RVJB59 ↗

• Researchers introduce a binding-to-release (BTR) strategy that triggers drug-conjugate payload release directly upon target binding, rather than requiring receptor-mediated endocytosis.
• The approach uses a new bioconjugation reaction, phosphorus(V)-phenol exchange (PhoPEx) — inspired by SuFEx click chemistry — engineered so that chemistry within the binding pocket itself cleaves the drug free once the conjugate engages its target.
• Because only a minority of drug targets support efficient endocytosis, this binding-triggered release could extend conjugate-based therapies to otherwise poorly internalizing targets.
• The authors describe proof-of-concept work with a conjugate targeting fibroblast activation protein (FAP), evaluated from in vitro settings through patient-derived tissue specimens.

A binding-to-release strategy for targeted anticancer drug delivery ↗

• Researchers report that 5-tBu-thalidomide, a chemically modified thalidomide analog, acts as a molecular glue that recruits the CRBN E3 ligase to drive potent, selective breakdown of FIZ1, a zinc-finger transcription factor linked to FLT3 signaling.
• FIZ1 contains eleven zinc-finger domains, several of which carry the degron sequence normally required for thalidomide-class drugs to engage, yet the compound acts almost exclusively through a single finger, zinc finger 8.
• Computational modeling of the CRBN–drug–FIZ1 ternary complex reveals the contacts that favor this domain over the others, explaining the selectivity.
• The work offers a template for rationally designing thalidomide-based glues that target individual zinc fingers within otherwise 'undruggable' transcription factors.

5-tBu-Thalidomide Is a Selective Molecular Glue Degrader of the Transcription Factor FLT3 Interacting Zinc Finger 1 (FIZ1) ↗