⚗️ Medicinal Chemistry

• Structure-based design delivered two 5:6 heterocyclic series with strong DDR1/DDR2 affinity and a promising kinome selectivity profile.
• An inhaled-by-design strategy then tuned potency, physicochemical and in vitro ADME properties toward lung-restricted compounds.
• Compound 25 combined antifibrotic activity in a TGF-β-induced in vitro fibrosis model with a favorable pharmacokinetic profile for local delivery.

Lung-Tailored Pyrrolo-pyrimidine DDR Inhibitors Designed for Optimized Local Delivery ↗

• Structure-based optimization of a 17-membered macrocyclic pyrazolo-triazine scaffold gave a potent CDK7 inhibitor.
• It showed no significant off-target activity across a panel of more than 400 kinases, addressing the poor selectivity of earlier CDK7 inhibitors.
• In cells it caused cell-cycle arrest, suppressed transcription and lowered c-Myc, especially in triple-negative breast cancer lines, with oral bioavailability and linear PK.

Discovery of Pyrazolo[1,5-a]-1,3,5-Triazine Derivatives as Potent, Highly Selective and Orally Available Macrocyclic CDK7 Inhibitors ↗

• ATP-competitive p38 inhibitors failed in the clinic partly through poor kinome selectivity, so the authors targeted the upstream kinase MKK3 through a non-ATP-competitive pocket.
• The lead, (R)-48, suppressed TNF-α production, was highly orally bioavailable and showed dose-dependent efficacy with clear PK/PD relationships in mouse ulcerative colitis models.
• Biophysical data (HDX-MS) were used to probe how the compounds engage MKK3.

Design and Synthesis of Novel, Non-ATP-Competitive MKK3 Modulators as Suppressors of TNF-α Production for the Treatment of Ulcerative Colitis ↗

• Appending an electrophilic monomethyl fumarate handle to a TTK inhibitor gave a single-warhead degrader, with no E3 ligand attached.
• The lead compound drove TTK degradation and showed stronger antiproliferative activity than the parent inhibitor across several cancer cell lines.
• Mechanistic work points to the E3 ligase RNF126, which the compound stabilizes in complex with TTK, leading to ubiquitination and proteasomal turnover.

Discovery of Threonine Tyrosine Kinase (TTK) Degraders Utilizing an Electrophilic Monomethyl Fumarate Handle ↗

• An electrophile-first screen, combined with X-ray crystallography, found a covalent hit that engages two cysteines (C85 and C111) of UBE2D2.
• Structure-guided SAR on the amide and ester groups removed binding to C111 while improving engagement of C85.
• The optimized analog inhibited UBE2D2 activity in vitro and suppressed proliferation of A549 lung cancer cells.

Electrophile-First Screening Identifies Covalent Aminothiazole Scaffold Inhibitors for Ubiquitin-Conjugating Enzyme UBE2D2 ↗

• The authors set out to improve on the only approved PDE4B-preferential drug, nerandomilast, which is only about 9-fold selective over PDE4D.
• YKS-34 is a potent PDE4B inhibitor with more than 1000-fold selectivity over PDE4A, PDE4C and PDE4D.
• It suppressed TGF-β-driven fibroblast activation and LPS-induced TNF-α release in vitro, and showed favorable PK with accumulation in lung tissue.

Discovery of YKS-34, a Highly Selective PDE4B Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis ↗

• CENPB, the sequence-specific DNA-binding protein at centromeres, is overexpressed in aggressive cancers, yet has no direct inhibitors.
• CENPB OligoTAC links a CENPB-binding oligodeoxynucleotide to an E3 ligase ligand, driving CENPB ubiquitination and proteasomal degradation, centromere disruption and apoptosis.
• It was active in NSCLC models resistant to first-, second- and third-generation TKIs, with little toxicity to normal cells, good serum stability and a favorable in vivo PK and tolerability profile.

Centromere-Targeting Chimeras for Combating Cancer Drug Resistance ↗

• The earlier tool compound NAcM-OPT blocked the DCN1–UBE2M interaction, was orally available and slowed xenograft growth, but carried significant hERG affinity that stalled development.
• The authors systematically modified the scaffold to cut hERG binding while keeping DCN1 engagement.
• Lead compound 110 matched the parent in biochemical and cellular potency, with better physicochemical properties and improved selectivity against hERG.

Reducing off-Target hERG Activity of First-Generation DCN1-UBE2M Interaction Inhibitors: Design, Synthesis, and Structure−Activity Relationships ↗

• Second-generation pan-FGFR inhibitors proved the concept but were limited by toxicities from inhibiting FGFR1, FGFR2 and FGFR4.
• Despite high structural homology across the family, structure-guided work has produced the first FGFR3-selective inhibitors to reach clinical evaluation.
• The Perspective covers the biological rationale, the design strategies behind the selectivity and emerging indications, including bladder cancer and achondroplasia.

FGFR3 Selectivity in Drug Discovery: Biological Rationale, Design Strategies, and Therapeutic Potential ↗

• A P. falciparum growth-inhibition screen identified a new pyrazine-2-carboxamide series for blood-stage malaria.
• Lead optimization improved anti-plasmodial potency and metabolic stability and reduced CYP2D6 inhibition risk, giving IWY357.
• A single dose was fully curative in a Pf-humanized SCID mouse model, resistance selection showed a high barrier, and the compound has progressed through GLP toxicology into phase 1.

Discovery of a Pyrazine-2-Carboxamide Derivative as a Potent Plasmodium falciparum Inhibitor with Potential for Single-Dose Cure ↗

• Covalent PLpro inhibitors were designed by combining an epoxysuccinamide warhead for Cys-111 with groove-binding features borrowed from non-covalent inhibitors.
• The compounds showed very high enzymatic potency and strongly reduced viral titres in cell culture.
• The flexible hydrazide linker was cleaved by hepatic carboxylesterases, and alternative linkers did not work, so the series is metabolically limited.

Discovery of Epoxysuccinates as Potent Covalent Inhibitors of SARS-CoV-2 Papain-like Protease ↗

• Aimed at CNS malignancies, the program replaced the carboxamide of saruparib with a series of heterocycles, targeting PARP1 over PARP2 to limit haematological toxicity.
• Caco-2 efflux, rather than the usual MDR1-MDCK assay, was used as a progression filter to select compounds with good unbound brain exposure.
• The lead compound was orally bioavailable and caused tumour regression in xenografts at a low dose, with a projected low clinical dose.

Discovery of Potent, Orally Bioavailable, and CNS-Penetrant 1,2,3-Triazolopyridinyl Piperazine-Based PARP1-Selective Inhibitors ↗

• Twenty PROTACs with varied E3 ligands, linkers and target binders were profiled in intracellular NanoBRET competition assays against cereblon and VHL tracers.
• Apparent potency spread widely when referenced to applied concentration, and passive Caco-2 permeability explained little of it.
• Correcting for measured intracellular unbound exposure shrank the spread dramatically, matching values from permeabilized cells.

Exploring the Relationship between Cell Permeability, Intracellular Exposure, and Target Engagement for PROTACs ↗

• ISG15 and its E1 enzyme UBA7 drive ISGylation, a pathway linked to treatment resistance in cancer, yet no inhibitors exist.
• The authors built an AlphaLISA assay for the ISG15–UBA7 interaction with strong robustness metrics for high-throughput use.
• A pilot screen of a small library gave a handful of hits, two of which also reduced ISGylation in cells.

A High-Throughput Screening Platform for the Discovery of Noncovalent Inhibitors of the ISG15–UBA7 Interaction ↗

• TD-DFT screening of a curated library of approved anticancer drugs picked out chromophore-bearing candidates with favourable photophysics.
• Mitoxantrone, pixantrone, daunorubicin and epirubicin generated reactive oxygen species on irradiation and showed enhanced cytotoxicity in breast cancer cells.
• One molecule thus supplies both the chemotherapy and the photodynamic effect, avoiding a two-component conjugate.

Repurposing Approved Chemotherapeutics as Intrinsic Photosensitizers for Single-Molecule Chemophototherapy ↗

• A series of Fe(III) compounds was optimized to Fe4, which was strongly cytotoxic to TNBC cells, and packaged as human serum albumin nanoparticles (HSA-Fe4).
• Structural analysis placed Fe4 in the IB subdomain of HSA, with His-146 coordinating the iron centre.
• In vivo, Fe4 and HSA-Fe4 curbed tumour growth and metastasis through Fenton-type chemodynamic therapy, ferroptosis and immune activation.

Developing a Ferric(III) Agent for Targeted Inhibition of Growth and Metastasis of Triple-Negative Breast Cancer Based on Human Serum Albumin by Chemodynamic Therapy-Driven Synergistic Therapy ↗

• Eighteen new 3H-1,5-benzodiazepines were made and tested against chloroquine-sensitive and resistant P. falciparum strains, with HepG2 cytotoxicity as a first selectivity check.
• Several compounds were active in the low micromolar range, with different members showing the best potency and the best selectivity.
• The two leads were only weak inhibitors of human G9a; docking, MM-GBSA and MD were used to propose binding to parasite PfSET3.

3H-1,5-Benzodiazepine Derivatives as Novel Antimalarial Agents: Synthesis, Biological Evaluation and Computational Target Exploration ↗

• The BPTF PHD–bromodomain cassette reads H3K4me3 together with K14 acetylation, a pairing confirmed by crystallography and shown to work cooperatively, including in cis.
• The authors report first experimental evidence of a ligand-induced conformational change between the two reader domains.
• A peptide–small-molecule conjugate, MJ-1, was built from these insights and inhibits both domains, addressing the usual ligandability problem of PHD fingers.

Bivalent Inhibitor Development for a Dynamic Epigenetic Tandem Reader Protein Using a Combinatorial Histone Code ↗

• Designed proteins target conserved epitopes in MYC, including intrinsically disordered motifs needed for its oncogenic activity.
• They bind MYC tightly in vitro; in cells they engage MYC, disrupt MAX pairing and reshape MYC-associated complexes.
• Expressing the binders curbed proliferation across several MYC-dependent hematopoietic, liver, pancreatic and patient-derived models, and depleted tumor cells in an orthotopic pancreatic model.

MYC targeted de novo binders impair tumor growth ↗

• mRNA display against the RAB27A effector-binding interface produced macrocyclic peptide hits, which were optimized into IMP2660.
• IMP2660 binds RAB27A tightly and disrupts RAB27A–effector interactions.
• Its co-crystal structure with active-state RAB27A, solved without any effector, maps the effector-binding surface for structure-guided design.

A potent macrocyclic peptide binder enables effector-free crystallization of the GTPase RAB27A ↗

• MRGPRX2 drives IgE-independent mast cell activation and is linked to urticaria, atopic dermatitis and pseudoallergic reactions.
• Scaffold hybridization and SAR gave pyrazolopyrimidine antagonists active in both Gq/IP1 and β-arrestin assays.
• Fixing solubility and CYP inhibition liabilities led to INCB187175, orally exposed across species, which blocked degranulation in primary human mast cells and mast cell activation in vivo.

Discovery of Pyrazolopyrimidines as Potent and Orally Bioavailable MRGPRX2 Antagonists ↗

• RhoJ is nearly identical to Cdc42 in sequence but carries a unique N-terminal extension, which simulations show forms an allosteric pocket on binding PAK3.
• Structure-based virtual screening against that pocket flagged the antifungal terconazole as a possible binder.
• In live cells, an optimized BRET2 biosensor showed terconazole reduces the RhoJ–PAK3 interaction in a dose-dependent way.

Identification and targeting of a novel drug pocket in the tumour angiogenesis regulator RhoJ ↗

• Several EGFR TKIs redesigned for blood-brain barrier penetration were studied by X-ray crystallography and potency assays.
• The BBB-enhancing groups engage varied regions of the EGFR kinase domains, and biochemical and cellular potency generally improved.
• Salt-bridge-forming moieties combined with certain halogen substitutions worked best, pointing to a 'two-for-one' design logic.

Structural Insights into Brain-Penetrant EGFR Tyrosine Kinase Inhibitors with Enhanced Potency ↗

• Cysteine-directed chemoproteomic screening found covalent ligands for Cys287, an allosteric pocket far from the thalidomide-binding site.
• Lead VVD-105917 broadly blocks degradation of neosubstrates driven by IMiDs and CELMoDs.
• Cryo-EM shows it traps cereblon in its open, inactive state, and ligand order matters. A previously reported ligand at the same site promotes closure instead, so the pocket is 'sign-switchable'.

Allosteric covalent inhibition of cereblon through cryptic cysteine targeting ↗

• Starting from the earlier lead PB94, the authors optimized the core, linker and cap of an indole-based hydroxamic acid series against HDAC11.
• The best compound, YP200, combines a secondary-amine linker with an adamantane surface-recognition cap.
• It showed high potency for HDAC11 with strong selectivity over other HDAC isoforms, and suppressed tumor growth in a patient-derived NSCLC xenograft.

Development of a Potent and Isoform-Selective HDAC11 Inhibitor with Anti-Tumor Efficacy against Non-Small Cell Lung Cancer ↗

• The 5-azaindole inhibitor 13 is potent against tau tubulin kinases 1 and 2 and active in cells.
• In-cell kinome profiling showed few off-targets; follow-up NanoBRET work narrowed them to CDK11A/B, CK1δ and PIKfyve.
• A close analogue, compound 5, lacks in-cell TTBK affinity and serves as a negative control; compound 13 blocks TTBK2 autophosphorylation and impairs primary cilia formation in RPE-1 cells.

Potent and Cell Active 5-Azaindole-based Tau Tubulin Kinase Inhibitors Disrupt Ciliogenesis ↗

• A cell-based high-content imaging screen was built to catch early mitotic spindle assembly defects.
• Run against a 3,520-compound cysteine-reactive library, it found a microtubule depolymerizer, a spindle-positioning disruptor and compounds that disturb spindle structure and chromosome alignment.
• Two hits caused mitotic arrest and reduced cancer cell viability (preprint; not yet peer reviewed).

Identification of Cysteine-Reactive Early Mitotic Inhibitors ↗

• Re-testing Elevenostat (JB3-22) against recombinant HDAC isoforms with two orthogonal HDAC11 assays showed only weak HDAC11 inhibition.
• Full HDAC1–11 profiling found much stronger inhibition of HDAC6 and HDAC10, plus class I enzymes, with HDAC11 the least sensitive isoform.
• Cellular readouts (tubulin and histone acetylation, reduced viability) matched HDAC6 and class I engagement, so past HDAC11 conclusions drawn from this compound need re-reading.

Elevenostat Is an HDAC6/Class I-Biased Multi-HDAC Inhibitor Rather than an HDAC11-Selective Chemical Probe ↗

• An automated patch-clamp screening cascade, built to deprioritize classic local-anesthetic pore binders, yielded an aminopyrimidine hit that was optimized into compound 6.
• Compound 6 combined balanced resting- and inactivated-state potency, selectivity over NaV1.5 and a tetrodotoxin-like isoform profile that includes NaV1.1.
• SAR pointed to the aminopyrimidine core and a methylene-linked aniline as key determinants of this profile.

A Nontoxin Aminopyrimidine Probe for Near State-Independent Na V 1.7 Inhibition ↗

• A virtual screen flagged EGFR inhibitors, including dacomitinib and gefitinib-like cores, as possible BAX binders.
• Systematic modification built a first SAR for BAX inhibition and reduced EGFR kinase activity considerably.
• The series showed better BAX inhibition in vitro, in cells and in iPSC-derived brain organoids, with drug-like properties.

Discovery of Anti-apoptotic BAX Inhibitors ↗

• Scaffold hopping from the BCL6 ligand BI-3802 gave a new tricyclic oxazinoquinolinone binder.
• Linker and CRBN-recruiter tuning produced compound 15, a PROTAC that degraded BCL6 quickly and potently, in a CRBN- and proteasome-dependent way.
• It strongly suppressed BCL6-dependent DLBCL cell growth, and oral dosing inhibited tumor growth in an OCI-LY1 xenograft without evident toxicity.

Discovery of Tricyclic Oxazinoquinolinone-Based BCL6 PROTAC Degraders with Potent Activity Against Diffuse Large B-Cell Lymphoma ↗

• Structure-based design and multiparameter optimization gave GTA182, a tricyclic amide with strong selectivity for MTAP-deleted over wild-type cells.
• Low efflux and tuned physicochemical properties delivered unbound brain exposure in the efficacious range.
• Orally dosed, it caused regression in MTAP-deleted xenografts and an orthotopic glioblastoma model, and early Phase I data reported good tolerability and intracranial tumor shrinkage.

Discovery of GTA182, a Novel CNS-Active Tricyclic Amide MTA-Cooperative PRMT5 Inhibitor for MTAP -Deleted Cancers ↗

• Virtual screening against the allosteric pocket seen in the SLC6A19/cinromide cryo-EM structure gave a starting hit.
• A second, partially overlapping pocket from a further cryo-EM structure inspired merged analogues, leading to a potent, selective, orally bioavailable compound 20.
• Compound 20 was weaker on mouse than on non-human primate SLC6A19, yet oral dosing raised urinary amino acid excretion dose-dependently.

Structure-Guided Discovery of Orally Bioavailable Allosteric SLC6A19 Inhibitors that Promote Urinary Amino Acid Excretion In Vivo ↗

• The team built a quantitative assay set around purified LRP1 ligand-binding domain 4, using fluorescence polarization, split luciferase and TR-FRET.
• Tau, RAP and a peptide ligand competed for overlapping binding sites with nanomolar-range affinities across formats.
• A screen on this platform identified small-molecule inhibitors of the interaction, a starting point against tau uptake and spread.

High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction ↗

• mRNA display against CHD4's SANT-SLIDE domain yielded small macrocyclic peptides that block its interaction with GATAD2A, a core step in building the NuRD complex.
• The screen pointed to a second binding site on CHD4; CDK2AP1 was confirmed to bind there, and the CHD4–GATAD2A–CDK2AP1 ternary complex structure was determined.
• Disrupting NuRD induces fetal hemoglobin, a validated therapeutic strategy for sickle cell disease and other β-hemoglobinopathies.

Macrocycle Screening against the C-Terminal Region of CHD4 Uncovers Its Role as an Interaction Hub in the Formation of the Nucleosome Remodeling and Deacetylase Complex ↗

• Ammonium salts built on natural cinchona alkaloids were explored as local anesthetics; the bicyclic quincoridine skeleton beat acyclic and monocyclic analogues.
• Lead CLA-1-3 blocked the rat sciatic nerve for more than 50 hours and potently inhibited voltage-gated sodium channels.
• A second compound, CLA-3-5, gave a sensory-selective block lasting up to about 3 hours at 0.30–0.60% concentration.

Cinchona Alkaloids-Derived Ammonium Salts for Long-Acting and Sensory-Selective Nerve Blockades ↗

• Structure-guided hybridization produced an indazole-based LRRK2 series; the initial piperidine compounds were potent but barely distinguished wild-type from G2019S mutant kinase.
• Replacing the piperidine with an octahydrocyclopenta[c]pyrrole widened the selectivity window while keeping good potency; compound 34 represents the new chemotype.
• The authors pitch it as an alternative starting point for next-generation, Parkinson's-directed LRRK2 inhibitors.

Discovery of G2019S Mutant Selective LRRK2 Inhibitors Based on an Indazole Octahydrocyclopenta[c]pyrrole-Based Hybrid Chemotype ↗

• Replaces the earlier phosphopeptide-based STAT6 PROTAC with non-peptide degraders designed for oral dosing.
• WW-210 degraded STAT6 at very low concentrations with a wide selectivity window over other STAT family members.
• It showed measurable oral bioavailability and degraded STAT6 in blood and spleen; in an atopic dermatitis mouse model it eased skin lesions, lowered serum IgE and reduced mast cell infiltration.

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

• Approved KRAS G12C drugs mostly trap the inactive GDP state and face resistance; this series targets the active GTP-bound state instead.
• A keto-indolizine HTS hit with an aniline-derived acrylamide binds Cys12 in the switch-II pocket; crystallography shows the warhead engaging the γ-phosphate of a GTP analogue.
• Optimization gave compound 17, orally bioavailable in preclinical species, which prolongs disruption of KRAS–cRAF binding and ERK signalling and produced complete regression in a pancreatic cancer xenograft.

Discovery of Novel Oral Covalent Inhibitors Targeting Active GTP-Bound KRAS G12C with Potent Antitumor Activity ↗

• Combines an electrophile-first covalent fragment screen with a ligand-first strategy to target lysines in the allosteric latch site of SHP2 phosphatase.
• Computational and experimental analyses support the binding mode, and the work yields what the authors call the first potent, cell-active allosteric covalent inhibitors at this site.
• It shows the latch site is covalently tractable, opening routes to new allosteric SHP2 chemotypes.

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

• The earlier hit BTP15 protects host cells from Mtb-induced death by blocking phagosomal escape through MprB inhibition, but had poor pharmacokinetics.
• New benzothiophene analogues were screened for MprB inhibition, microsomal stability, toxicity and ex vivo efficacy in THP-1 and MRC-5 cells.
• The aim is a virulence-blocking route that avoids killing the bacterium directly, which may reduce resistance pressure.

Antivirulence Benzothiophenes Inhibit Intracellular Mycobacterium tuberculosis by Targeting the Sensor Histidine Kinase MprB ↗

• TFEB, a transcription factor long seen as undruggable, was approached starting from eltrombopag, which has weak TFEB inhibitory activity alongside its Tpo-R agonism.
• SAR optimisation gave DCL1191, which binds TFEB, disrupts TFEB–DNA binding and shows reduced Tpo-R and MITF activity; modelling and mutagenesis support the binding mode.
• It represses TFEB target genes, blocks autophagic flux and is orally bioavailable, with activity in autophagy-hyperactivated glioblastoma cells.

Development of DCL1191 as a Potent, Selective and Orally Bioavailable Inhibitor for Autophagy-Associated Transcription Factor EB (TFEB) ↗

• Second-generation HDAC6 inhibitors were designed from X-ray structures of earlier compounds bound to the zebrafish HDAC6 catalytic domain.
• Co-crystal structures of two leads showed engagement of S531 in the L2 loop; cells showed raised acetylated tubulin without a clear histone acetylation change.
• One lead cut A549 viability in 2D and 3D culture through pro-autophagic signalling and also affected phase-separation behaviour.

Structure-Based Design of HDAC6 Inhibitors Targeting the L2 Pocket: Modulating Autophagy and Liquid−Liquid Phase Separation in Lung Cancer ↗

• PDIA3, an ER oxidoreductase involved in folding glycosylated viral envelope proteins, is an underexplored host target for antivirals.
• A new N-hydroxyindole-2-carboxamide class, exemplified by AV22, inhibits PDIA3 and shows broad activity against major human respiratory viruses.
• In coronavirus-infected cells AV22 raised release of non-infectious particles and reduced disulfide bond formation in spike.

Development of N-Hydroxyindole-2-Carboxamides as New Host-Targeted Broad-Spectrum Antiviral Agents Against Human Respiratory Viruses ↗

• A three-cycle, peptide-like DEL of 403,200 compounds was built, with a chemical space model of 4,774 commercial amino acids used to find under-represented building blocks.
• Affinity selections were run against three targets to compare library performance.
• Selection against carbonic anhydrase II recovered the known sulfonamide pharmacophore, supporting the computational design approach.

Design, Synthesis, and Comparative Selection Analysis of a Chemically Diverse Peptide-Like DNA-Encoded Library ↗

• Host-directed dual inhibition of PI4KIIIβ and HDACs had not previously been reported for hepatitis C, where resistance to direct-acting antivirals remains a concern.
• A series of thiazolamide-based dual inhibitors was designed, synthesised and evaluated.
• Lead compounds showed potent enzymatic inhibition of both targets together with anti-HCV activity.

Discovery of Thiazolamide-based PI4KIIIβ/HDAC Dual Inhibitors with Potent Activity against Hepatitis C Virus ↗

• SAR work identified D4, which binds STING directly and blocks its oligomerization and downstream TBK1/IRF3 signalling.
• In macrophages it restored phagocytosis, autophagic flux and mitochondrial function while dampening NLRP3-linked pyroptosis.
• D4 was orally exposed and well tolerated at high dose, and cut pancreatic injury and enzyme levels in a caerulein/LPS model; STING knockdown looked similar.

Discovery of Novel STING Inhibitors for the Treatment of Severe Acute Pancreatitis ↗

• The natural product millepachine was fused with a key HDAC-inhibitor pharmacophore to build dual tubulin/HDAC inhibitors.
• Lead compound 6 was broadly antiproliferative across 12 cancer lines, inhibited tubulin polymerisation and HDAC8, and was selective for HDAC8 over HDAC1, 4 and 6.
• It suppressed tumour growth in an ovarian cancer xenograft with a favourable safety profile.

Discovery of a Novel Dual Inhibitor Targeting Tubulin and Histone Deacetylase 8 for Treatment of the Ovarian Cancer ↗

• A solid-phase route enabled systematic variation of VHL ligand, exit vector and linker in vorinostat-derived HDAC6 PROTACs.
• Longer, semi-rigid linkers gave the best degradation; the lead compounds degraded HDAC6 preferentially in MM.1S and MV4-11 cells.
• A matched non-degrading control with similar HDAC inhibition was clearly less antiproliferative, pointing to degradation itself as the driver.

Solid-phase synthesis and structure-degradation relationships of VHL-recruiting PROTACs for preferential histone deacetylase 6 degradation ↗

• Six PROTACs built on ferulic acid, a weakly active natural product, were tested for TLR4 degradation and migration in HUVECs.
• The lead, FP-4, degraded TLR4 and dampened TLR4/MyD88–NF-κB signaling plus TNF-α, ICAM-1 and VCAM-1 expression.
• Protection was also seen in zebrafish, extending PROTAC use beyond oncology.

Enhancing Natural Product Therapy with PROTACs: Targeted Degradation of TLR4 Confers Potent Endothelial Protection ↗

• SAR optimization of earlier virtual-screening hits, themselves derived from the antagonist NIBR189, gave full GPR183 agonists with complete G protein bias.
• The lead, TUG-2604, matches the endogenous oxysterol 7α,25-OHC in potency and efficacy without recruiting β-arrestin2.
• It failed to drive human dendritic cell migration on its own and blocked migration induced by the oxysterol.

Development of Potent G Protein Pathway-Biased GPR183 Agonists ↗

• Scaffold-hopping virtual screening produced a diaryl pyrimidine-guanidine series against the JmjC demethylase KDM6B, which is overexpressed in cervical cancer.
• The optimized lead matched GSK-J4 in enzyme potency but is non-competitive with 2-oxoglutarate, a different binding logic from most JmjC inhibitors.
• Despite pan-KDM activity in vitro, it selectively raised H3K27me3 in C33A cells and slowed xenograft growth.

Discovery of Diaryl Pyrimidine-Guanidine Derivatives as Jumonji C Domain-Containing Lysine Histone Demethylase (KDM) Inhibitors with In Vivo Anti-Cervical Cancer Activity ↗

• SAR and property work on the 3-(biphenylethynyl)-1H-indazole scaffold behind CDD-2807 targeted its poor kinetic solubility.
• CDD-3094 kept nanomolar cellular potency while gaining solubility, lowering hERG liability and showing a clean broad kinase panel.
• A co-crystal structure guided changes against the main off-target CLK4, giving a strongly selective biochemical tool whose cellular potency dropped.

Design, Synthesis, and Pharmacological Profiling of Serine/Threonine Kinase 33 (STK33) Inhibitors for Nonhormonal Male Contraception ↗

• Donepezil-based derivatives were designed and made as dual inhibitors of human butyrylcholinesterase and fatty acid amide hydrolase.
• Lead G15 inhibited both enzymes in a balanced way, with sub-micromolar to low-micromolar activity.
• It showed measurable selectivity over the carboxylesterases CES1 and CES2, a common liability for serine-hydrolase inhibitors.

Design, Synthesis and Evaluation Donepezil-Based Dual BuChE/FAAH Inhibitors for Alzheimer's Disease Therapy ↗

• Structure-guided hybridization of an indazole with an octahydrocyclopenta[c]pyrrole gave a new LRRK2 inhibitor chemotype for Parkinson's disease.
• Early piperidine-containing analogs were potent but barely distinguished wild-type from G2019S LRRK2.
• Swapping the piperidine for the fused bicyclic amine was the change introduced to widen that selectivity window.

Discovery of G2019S Mutant Selective LRRK2 Inhibitors Based on an Indazole Octahydrocyclopenta[c]pyrrole-Based Hybrid Chemotype ↗

• A Trojan-horse design hijacks bacterial iron uptake to move a β-lactam payload across the Gram-negative outer membrane.
• Ampicillin was conjugated to mono-catecholate, bis-catecholate and catecholate–hydroxamate siderophores and the series compared.
• The bis-catecholate conjugate is reported as the selective one, extending ampicillin's reach to multidrug-resistant P. aeruginosa.

A Selective Bis-Catecholate Siderophore-Ampicillin Conjugate Expands Activity against Multidrug-Resistant Pseudomonas aeruginosa ↗

• The oxidation-sensitive thioether in an IL-11-binding peptide was replaced with a lactam bridge, with linker length screened systematically.
• The optimized analog 4L6–16 bound IL-11 with good affinity and antagonized it more strongly than the starting peptide.
• It showed renoprotective effects in both cell and animal models of renal fibrosis.

Development of a Lactam-Bridged Peptide as Interleukin-11 Antagonist for Renal Fibrosis Treatment ↗

• Guided by earlier crystal structures, kinetic target-guided synthesis was used to assemble inhibitors of the P. aeruginosa virulence factor elastase LasB.
• Extensive SAR gave hydroxamic acid inhibitors with very high potency and good selectivity over a panel of human off-targets.
• The compounds protected lung epithelial cells from LasB damage, showed in vivo efficacy, and reached lung exposure above their biochemical potency.

Kinetic Target-Guided Discovery of Selective Nanomolar Hydroxamic Acid–Based Inhibitors of Pseudomonas aeruginosa Elastase LasB ↗

• The charged amino bisphosphonate inhibitor ARC39 of acid sphingomyelinase was masked to improve cell entry.
• Masked derivatives reached nanomolar activity in cells, about two orders of magnitude better than the parent.
• Cell uptake, stability and related properties were characterized in detail.

Masked Bisphosphonate Inhibitors of Acid Sphingomyelinase: Improved Cell Penetration and Potency ↗

• Only temozolomide and vorasidenib are approved brain-permeable, orally available drugs for brain cancers, so the team sought new brain-penetrant options.
• SAR work yielded a new class of highly brain-penetrant tubulin ligands; co-crystal structures confirm colchicine-site binding, with the tubulin βT7 and αT5 loops flipped relative to the colchicine-bound state.
• SAR showed high sensitivity to substitution with few indispensable moieties, leading to compound 40 as the clinical candidate.

Discovery and Optimization of a Novel Brain-Penetrant Colchicine-Binding Site Ligand for Treatment of Glioma ↗

• DNMT1 drives fibrogenesis through both catalytic and non-catalytic mechanisms, so the team built PROTAC degraders starting from DC-517 to hit both at once.
• Lead compound B7 mediates ubiquitin-proteasome degradation of DNMT1, lowers global DNA methylation and suppresses profibrotic responses in vitro.
• In vivo, B7 reduced DNMT1 levels and attenuated liver fibrosis, with less collagen deposition and better hepatic function.

Discovery of Potent, Selective DNMT1 PROTAC Degraders: Simultaneous Blockade of Catalytic and Non-Catalytic Functions for Liver Fibrosis Therapy ↗

• ENPP1 hydrolyzes cGAMP in the tumor microenvironment and so dampens STING-driven antitumor immunity.
• Inspired by the phosphate-based inhibitor STF-1084, the team made non-nucleotide inhibitors with a boronic acid zinc-binding group, leading to compound 36, which stays potent across pH.
• Compound 36 boosted cGAMP-mediated STING activation in vitro and gave tumor growth inhibition as monotherapy in a syngeneic CT26 model, with a synergistic effect alongside oxaliplatin and no observed toxicity.

Development of pH-Resilient Boronic Acid ENPP1 Inhibitors for STING-Mediated Cancer Immunotherapy ↗

• KTT-1 (compound 12) was identified as HDAC2-selective by evaluating both thermodynamics and kinetics of enzyme–inhibitor binding, rather than affinity alone.
• Crystallography of HDAC2 with the compound, plus quantum chemical calculations on model compounds, suggests its 2-furanyl group drives the selectivity.
• In cells it preferentially inhibited HDAC2 over the highly homologous HDAC1 and promoted neurite outgrowth; in stress-vulnerable mice it improved memory and depression-like behavior.

Discovery of an HDAC2-Selective Inhibitor via Enzyme−Inhibitor-Binding Thermodynamics/Kinetics as a Prospective Neurological Disorder Drug ↗

• Pan-Hsp90 inhibitors stalled clinically because of their broad inhibition, so Hsp90β-selective indazolone compounds have been pursued, though earlier ones needed long optimization to become drug-like.
• This work modifies the northern indazolone fragment and the southwestern appendage at the same time, testing whether the best traits of each region can be combined.
• The resulting chimeric inhibitors retain Hsp90β affinity and selectivity while shifting key pharmacokinetic parameters.

Chimeric Hsp90β-Selective Inhibitors Confer Enhanced Affinity, Selectivity, and Drug-Like Properties ↗

• A bicyclopiperazine hit from a DNA-encoded library was optimized by structure-guided design into compound 1.5 (MAGLi 432), a reversible MAGL inhibitor.
• The compound combines high potency, selectivity over other serine hydrolases and CNS drug-like properties, with a favorable oral half-life in rats.
• It inhibited MAGL in human brain homogenate and worked in mouse neuroinflammation models; the campaign was steered by a translational "Five-Star Matrix" framework.

Translational Application of the Five-Star Matrix for the Structure-Guided Optimization of a Bicyclopiperazine DEL Hit into Bcpz 1.5: A Potent Monoacylglycerol Lipase Inhibitor with Functional Inhibition in Human Brain Homogenate and Efficacy in Neuroinflammatory Models ↗

• QPCT and Golgi-bound QPCTL convert N-terminal glutamines to pyroglutamate, affecting Aβ oligomerization, chemokine stability and CD47–SIRPα signaling.
• A virtual screen selecting under 0.1% of an in-house library, based on similarity to bioactive conformations of known inhibitors, delivered new chemotypes and sped up hit discovery.
• Structure-guided optimization of a quinazolidinone series gave the cellular tool compound BI-3614, with improved activity over earlier inhibitors.

Accelerated Hit Identification and Optimization of a Novel Class of Cellularly Active QPCT/L Inhibitors ↗

• Using 403 SARS-CoV-2 main protease structures from the open COVID Moonshot campaign, the authors asked how many new crystal structures are worth collecting.
• Similar reference ligands give the best pose prediction, and success plateaus at roughly five structures per Bemis-Murcko scaffold, exceeding 95% for the lead series.

How Many Crystal Structures Do You Need to Trust Your Docking Results? ↗

• Oral sGC stimulators can cause systemic hypotension and worsen ventilation-perfusion mismatch in PH-COPD, motivating a lung-restricted design.
• SAR and PK work identified high systemic clearance and low permeability as the key drivers of pulmonary selectivity.
• Compound 15 (frespaciguat, MK-5475) is a very potent stimulator with long target residence time and more than 200-fold unbound lung-to-plasma exposure after inhalation, with efficacy in a rat chronic hypoxia model.

Frespaciguat (MK-5475): A Novel Inhaled Soluble Guanylate Cyclase Stimulator for Pulmonary Hypertension Associated with COPD ↗

• Starting from a literature-derived PERK inhibitor of moderate potency but good kinase selectivity and PK, the team ran a lead optimization campaign steered by log D and lipophilic ligand efficiency.
• This produced APL-11056 (compound 49), a potent and selective PERK inhibitor with excellent in vivo pharmacokinetics.
• High permeability is linked to a fluorine alpha to the core benzamide, which appears to limit efflux-transporter recognition.

Discovery of a Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) Inhibitor Suitable for Clinical Progression ↗

• POLQ drives microhomology-mediated end joining, making it a synthetic-lethal target in homologous-recombination-deficient cancers.
• Optimizing a weak biochemical hit gave benzimidazole/purine inhibitors; compound 37 is potent, selective and orally active.
• In BRCA2-deficient DLD-1 cells it was antiproliferative and boosted olaparib, with no effect in HR-proficient cells; chronic oral dosing with olaparib regressed xenografts.

Discovery of a Novel Series of Benzimidazoles/Purines as Potent, Selective and Orally Active Inhibitors of the DNA Polymerase Activity of POLQ ↗

• Covalent sulfonium modification of the natural pneumocandin B0 scaffold gave derivatives active against Candida and able to reverse innate Cryptococcus neoformans resistance (MIC as low as 2 μg/mL).
• The modification raised fungal membrane permeability and caused depolarization while strengthening glucan synthase inhibition.
• Leads 3h and 5h showed low resistance potential, good safety and PK, and in vivo antifungal efficacy.

Sulfonium Modification of Echinocandins: An Effective Strategy to Combat Intrinsically Resistant Cryptococcus via Membrane Disruption and Enhanced Cell Wall Biosynthesis Inhibition ↗

• ATP-competitive inhibitors struggle to separate ULK1 from the near-identical ULK2, so the authors built cereblon-recruiting degraders instead.
• Structure-guided optimization gave MR-9036, which degrades ULK1 without touching ULK2 or IMiD neo-substrates, with ternary complex formation and proteasome dependence confirmed.
• After compound washout it kept autophagy suppressed longer than the clinical ULK1/2 inhibitor DCC-3116, with antitumor activity in KRAS G12C NSCLC models.

Discovery and Optimization of Isoform Selective ULK1 Degraders to Enhance Antitumor Activity in KRAS-Mutant Cancer ↗