Peptides & macrocycles
24 articles
Macrocyclic pyrazolotriazine CDK7 inhibitor combines kinome-wide selectivity with oral exposure
- 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.
A clean result across 400+ kinases is rare for CDK7, where the covalent field has leaned on THZ-type warheads. A non-covalent macrocycle that is also orally exposed is the profile I'd actually want to pick up for a transcriptional-addiction indication. The open question is on-target toxicity, since selectivity among kinases won't spare you CDK7's role in normal transcription.
mRNA-display macrocycle IMP2660 gives the first effector-free RAB27A structure
- 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.
The crystallography chaperone angle is the underrated payoff: wild-type RAB27A only crystallized with its effector, so a clean macrocycle-bound structure unlocks soak-in and fragment work. Whether IMP2660 itself is more than a tool is another matter, since permeability for a nonapeptide-sized macrocycle against an intracellular GTPase is the obvious hurdle.
A potent macrocyclic peptide binder enables effector-free crystallization of the GTPase RAB27A ↗
mRNA-display macrocycles reveal CHD4 as an interaction hub in the NuRD complex
- 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.
One selection campaign delivering both hits and biology is a nice outcome. Macrocycles sitting on a protein–protein interface are rarely drug-like as they stand, so my question is whether the ternary structure lets us shrink them toward something cell-permeable; the second site on CHD4 gives another handle for that. I'd also want to see selectivity against related remodelers.
In silico building-block selection widens the diversity of a 403,200-member peptide-like DEL
- 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.
Recovering the sulfonamide on CA II is the expected sanity check, not proof of lead-like coverage. Peptide-like DELs often return big, polar hits, so what I'd judge is how many selected compounds sit in usable property space off-DNA, and how the two other targets behaved.
Lactam bridge replaces oxidation-prone thioether in an IL-11 antagonist peptide
- 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.
Swapping a thioether for a lactam is a textbook peptide-stability fix, and it's encouraging that it also improved antagonism rather than just shelf life. Binding in the mid-nanomolar range leaves room to tighten, and proteolytic stability in plasma is the next number I'd ask for.
Development of a Lactam-Bridged Peptide as Interleukin-11 Antagonist for Renal Fibrosis Treatment ↗
A macrocyclic BI-4020-based PROTAC degrades C797S-resistant EGFR
- HQY1480 is a PROTAC built on the macrocyclic fourth-generation EGFR inhibitor BI-4020, with the linker and E3 ligand optimized systematically.
- It degraded several clinically relevant EGFR mutants at low nanomolar concentrations, and proteomics showed no detectable off-target degradation.
- It outperformed BI-4020 in xenografts, including osimertinib-resistant models, and degraded EGFR in patient-derived xenografts.
Starting from a macrocycle rather than a classical TKI is the smart move: it sidesteps the poor PK and selectivity that EGFR PROTACs usually inherit from their warheads. I'd want to see how the degrader holds up against compound-specific resistance mutations, and whether the favorable PK survives scale-up beyond mouse.
First synthetic PAPP-A inhibitors dampen IGF-1 signaling in cells and in vivo
- PAPP-A is a secreted metalloproteinase that cleaves IGF-binding proteins to control local IGF signaling, offering an alternative to IGF-1R targeting.
- Inhibitors were built on an IGFBP-5-derived anchor sequence, with the scissile bond replaced by phosphinate or phosphonate groups, giving potent and selective compounds.
- Cryo-EM showed how they bind the active site, and they blocked IGFBP-4 and IGFBP-5 cleavage.
- They suppressed IGF-1 signaling in A549 cells, comparably to stanniocalcin-1, and inhibited Papp-aa-dependent signaling in vivo.
Swapping the scissile bond of an IGFBP-5 anchor sequence for a phosphinate or phosphonate is classic transition-state mimicry, and a cryo-EM pose would validate the zinc-binding hypothesis. Going after the protease rather than IGF-1R is smart for selectivity. I'd want Ki values against related metalloproteinases, and cell permeability and stability of these peptidic leads, before trusting the in vivo claim.
Novo bets up to $1.4B on Orbis's oral macrocycle platform
- Orbis Medicines signed a multi-target discovery and license deal with Novo Nordisk worth up to $1.4B in upfront and milestone payments plus tiered royalties.
- Novo also takes a strategic equity stake in the private Copenhagen company; this is Orbis's first pharma partnership.
- The work uses Orbis's AI-enabled nGen platform to make macrocycles aimed at turning injectable cardiometabolic therapies into orals.
- Orbis reported preclinical oral bioavailability up to 18%; targets and disease areas beyond cardiometabolic were not disclosed.
This is Novo hedging its oral strategy beyond small-molecule GLP-1s and oral semaglutide: macrocycles are the bet that peptide-like potency can survive the gut. The headline number is mostly milestones, so the real signal is the equity stake and a multi-target structure that lets Novo test the platform cheaply. Lilly is also an Orbis backer, which tells you both obesity leaders want the same oral-peptide option.
Lilly-backed Orbis does up to $1.4B macrocycle deal with Novo ↗
BmTACs Ride Age-Upregulated Transcytosis to Deliver a ROS-Activated DAPK1 Degrader into the Brain
- Brain delivery is the main barrier for degraders in neurodegeneration; BmTACs attach a macrocyclic peptide shuttle that exploits caveolae-mediated transcytosis, which rises with age in brain endothelium.
- A reactive-oxygen-species-responsive cage on the VHL ligand keeps the PROTAC inactive until it reaches high-ROS tissue.
- The platform is designed to remove activated DAPK1 selectively in the aging brain.
Two gating layers, shuttle for entry and ROS cage for activation, is clever systems design, but it moves the problem from medicinal chemistry to conjugate CMC and PK. I'd look hard at the unmasked-PROTAC fraction in periphery and at the shuttle's dependence on aged-endothelium biology, which could narrow the patient window. A real step for CNS degraders if the in vivo data hold up.
Repeating a Five-Residue Melittin Fragment Gives Non-Haemolytic β-Sheet Antibacterial Peptides
- 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.
Shrinking melittin to a tandem repeat and flipping it from helix to sheet is a neat way to decouple killing from lysis. The intracellular mode of action is the interesting part, since it points away from the membrane-disruption liabilities that kill most AMPs in the clinic. I'd still want protease stability and plasma binding data before believing the in vivo window.
Albumin Binder Keeps αvβ6 Radiotracer in Pancreatic Tumors Longer
- 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.
Tumor washout is what sinks most small-peptide radioligands, and an albumin binder is the standard fix, but the balance is delicate: too much binding and the blood pool swamps your contrast. Pairing it with a very polar Asp2 linker looks like a sensible way to buy retention without paying in background. The real test is kidney and marrow dose with 177Lu.
Two-Step Route Expands Warhead Diversity in Covalent Genetically-Encoded Macrocycle Libraries
- 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.
Regioisomer scrambling in one-pot warhead installation is exactly what kills confidence when you're deconvoluting covalent DEL hits — you can't tell if a signal is real or an artifact of a messy electrophile mixture. Decoupling cyclization from Knorr-pyrazole warhead chemistry means finally screening exotic, more reactive electrophiles beyond the usual acrylamide/chloroacetamide workhorses without second-guessing every hit's identity.
Imidazolium Amino Acids Proposed as Bioisosteres for Methylated Lysine and Arginine Residues
- 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.
A non-hydrolyzable Kme3/Rme2 mimic solves a genuine headache—native methylated peptides get erased by demethylases or clipped by proteases mid-assay, muddying SAR. If ring substitution tunes affinity without killing permeability, this is a genuine alternative scaffold for reader-domain PPI inhibitors and arginine-free CPPs, not just another quaternary-ammonium curiosity—worth testing against our own Kme3 reader panel.
Triazole-Stapled Peptides Merge Opioid and NPFF Signaling for Long-Lasting Peripheral Pain Relief
- 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.
Stapling DN-9's opioid core with triazoles to lock the bioactive turn, then bolting on an NPFF pharmacophore via chimeric conjugation, gets you μ/κ/NPFF polypharmacology without a small-molecule fragment-merging slog — clever scaffold logic. Layering G-protein-biased μ signaling on top of peripheral restriction stacks two independent side-effect levers in one peptide, though I'd want to see the stapling's SAR tolerance before calling it tractable.
Antibody-Inspired Peptides Take Aim at Flu's Fusion Machinery
- 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.
FI6v3 and CR9114 are smart hotspots to steal from, and a compact L-peptide is far more tractable to make and dose than the antibody it's mimicking. But stem-directed HA binders have a rough history against escape mutants — durability of coverage across drift, not just initial fusion-blocking potency, is the question I'd want answered before getting excited about a therapeutic path.
Antibody Hotspot-Centric de Novo Design of Peptide Inhibitors of Influenza A Virus Membrane Fusion ↗
All-Atom Receptor-Aware Deep Learning Model Advances De Novo Peptide Binder Design
- Researchers developed REAPS, a geometric graph neural network for designing peptide binder sequences that models the target receptor as a fully observable, all-atom structural context, rather than relying on backbone geometry alone as typical inverse-folding methods do.
- In head-to-head evaluations against the widely used inverse-folding model ProteinMPNN, REAPS showed improved sequence recovery, structural fidelity, and interface-level biophysical properties for both linear and macrocyclic peptide binders.
- The team paired REAPS with structural hallucination in a closed-loop de novo design pipeline to generate novel peptide candidates without requiring a known starting scaffold.
- Candidates produced through this pipeline were synthesized and tested against the neurokinin-3 receptor (NK3R), where they showed experimentally confirmed functional activity.
Sequence recovery and "improved structural fidelity" benchmarks against ProteinMPNN are nice, but what I actually care about is whether the closed-loop hallucination + REAPS pipeline produced binders without a template scaffold — that's the real test, and NK3R hits with confirmed functional activity clear that bar. All-atom receptor context should, in principle, capture side-chain packing and H-bond networks that backbone-only inverse folding misses, which matters a lot for macrocycle design where conformational preorganization is everything. Before I'd plug this into a campaign: what's the actual hit rate and binding affinity on those synthesized NK3R peptides, not just "functional activity"? And does performance hold on a GPCR-like target outside training distribution, or is this another tool that shines on its own benchmark set and stalls on my target. Worth piloting on a live target before I swap out MPNN wholesale.
SELLAS's Phase 3 AML Immunotherapy Trial Expected to Fail, Per STAT Report
- SELLAS Life Sciences' galinpepimut-S (GPS) is a WT1-targeting peptide immunotherapy.
- The pivotal Phase 3 REGAL trial enrolled more than 100 acute myeloid leukemia (AML) patients in second remission, randomized to GPS versus physician's choice of treatment, with the primary goal of demonstrating improved overall survival.
- The trial is event-driven, requiring 80 patient deaths before a final analysis can be conducted; reporting indicates the event count is nearing that threshold.
- The trial's conclusion has been delayed by nearly a year.
- Per STAT News reporting by biotech columnist Adam Feuerstein, the long-delayed REGAL trial is expected to end in failure, with GPS not expected to show a survival benefit over standard of care.
- A negative outcome would represent a significant setback for SELLAS's lead clinical program.
Nearly a year late to hit its death-count threshold — that delay is the real signal in this story, not a footnote. Event-driven trials that take longer than planned to accrue events are rarely good news: if the treatment arm were meaningfully extending survival, events would accrue slower and the delay would read as encouraging, not ominous. That REGAL is reportedly headed for failure fits a pattern, not an anomaly. This is SELLAS's lead asset, so a negative confirmatory readout isn't a pipeline setback — it's closer to an existential one for a small-cap with limited runway and few near-term catalysts to fall back on. It also adds another data point to WT1-targeting peptide vaccines' long, mostly disappointing history in AML, a mechanism that has struggled to translate immunogenicity into survival benefit across multiple sponsors. Expect a sharp reassessment of remaining pipeline value, cash runway, and financing options once/if this is confirmed.
A Sellas immunotherapy study, long delayed, will end in failure ↗
New Fragment-Based Docking Method Targets Long, Flexible Peptide Ligands
- Researchers built STELLAR, a new docking workflow aimed at a persistent problem: current tools poorly handle long, highly flexible biopolymer ligands, including peptides exceeding roughly ten subunits, because of their vast conformational freedom.
- STELLAR splits such ligands into smaller fragments, docks each one separately, then reassembles them into a full-length, physically realistic pose, using established software including GNINA, RDKit, and GROMACS for refinement.
- Tested against known peptide-protein complexes from the Propedia database and the Protein Data Bank, the workflow reproduced experimentally observed binding poses with high accuracy.
- Compared with other state-of-the-art docking tools, it runs mainly on CPUs, scales linearly with ligand length, executes faster, and includes a ranking metric suited to high-throughput screening of long-chain polymer-protein interactions.
Ten residues is roughly where my patience with standard docking runs out — past that, chains have so much conformational freedom that I end up either restraining everything by hand or giving up on the exercise. Fragment-then-reassemble is a sensible workaround, and leaning on GNINA/RDKit/GROMACS instead of a black-box neural net means I can actually inspect intermediate poses. CPU-only, linear scaling is the detail that matters most day-to-day: no GPU queue, no cloud bill, just run it on the workstation overnight for a stapled-peptide library. Most ML docking tools give me a score with no real confidence handle for ranking; a purpose-built ranking metric for long-chain ligands is genuinely missing elsewhere. That said, Propedia/PDB benchmarks are known complexes — reproducing a crystal pose isn't the same as correctly ranking novel binders against a target with no solved structure. Worth a pilot run, not a blind swap-in.
STELLAR: A Fragment-Based Docking Workflow for Highly Flexible Long-Chain Biopolymers ↗
BBB-Crossing PROTAC Macrocycles Selectively Degrade DAPK1 in Aging Alzheimer's Brains
- 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.
The caged VHL ligand is the clever bit — redox-triggered decaging means the warhead sits as a prodrug until it hits oxidative-stress tissue, which could finally address the peripheral-toxicity problem that's dogged systemic PROTAC dosing. I want the counter-screen though: how much decaging leaks in non-lesion CNS tissue over chronic dosing, and does 'activated DAPK1' selectivity hold in human proteoform or is that mouse-conformer-specific? The macrocyclic peptide-small molecule hybrid is a brutal synthesis — SPPS, macrocyclization, PROTAC conjugation, yield bleeding at every step — this is proof-of-concept, not a scalable series. Exploiting age-upregulated transcytosis instead of fixed RMT receptors (transferrin, insulin) is the real advance over TfR-shuttle degraders; the open question is whether that route is druggable across disease stages, not just aged models.
Bifunctional Pyridine Linker Enables Sequential, Stable Bioconjugation for ADCs and Peptides
- 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.
Maleimide-cysteine chemistry's dirty secret is retro-Michael instability — payload leaches back into circulation, and DAR isn't as fixed as the spec sheet claims. This bifunctional pyridine/thianthrenium scaffold attacks that head-on: the resulting aryl-thioether is non-chiral and hydrolytically stable, so no diastereomer mixtures and no slow linker exchange with serum thiols. Sequential chemoselectivity — amine coupling first, cysteine second, off one handle — is a real practical upgrade for installing orthogonal payloads/tags, not just another NHS-ester variant. What earns my attention is that they didn't stop at peptide-stapling demos: a tunable-DAR HER2 ADC analog of MRG002 with improved serum payload retention versus conventional linkage is the kind of proof point that actually moves a methodology from academic curiosity toward something worth piloting. Thianthrenium reagent scale-up and cost will decide if it ever displaces maleimide on a GMP line.
Cyclic Peptide PROTACs Knock Down HIF-1α — Until Hypoxia Outpaces Them
- 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.
Smart move folding the VHL ligand and linker into a bifunctional amino acid for direct SPPS incorporation — that sidesteps the PEGylation/conjugation bottleneck that makes cyclic peptide degraders such a pain to iterate on, and it turns linker SAR into a synthesis-cycle variable instead of a separate coupling step. The SICLOPPS-derived warhead is a nice proof that a cyclic peptide can grip a transcription-factor surface a small molecule can't easily touch, so on chemotype comparison this favors the peptide side. But the real flag for my own work is the hypoxia dropout: ternary complex still forms, HIF-1α still gets marked, degradation just can't keep up. That's not a binding problem I'd fix by optimizing the VHL warhead — it's a turnover-rate problem, and it says something uncomfortable about any PROTAC campaign against a target with fast resynthesis kinetics.
Cyclic Peptide PROTACs Restore VHL-Mediated HIF-1α Degradation in Hypoxia ↗
A SuFEx Click Reaction Streamlines DNA-Encoded Macrocyclic Peptide Libraries
- 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.
On-DNA chemistry is where good click reactions go to die — CuAAC needs copper that chews up your barcode, most coupling chemistry leaves truncation side-products you chase off HPLC for weeks. SuFEx actually respects the constraints: no metal, no coupling reagent, just a phenol and an ArSO2F sitting in basic water reacting with each other. That's "click" chemistry finally earning its name in DEL work instead of just borrowing the marketing. High conversion with zero catalyst also means boring QC, in the best sense — fewer truncated/uncyclized side-populations polluting the pool means the hits you pull downstream are more likely real signal, not artifacts of your worst-yielding step. For macrocycles — the space between small molecules and biologics everyone wants but few can screen efficiently — a clean cyclization step is what lets you scale diversity without sacrificing quality. This is the unglamorous methods advance that keeps unlocking new DEL generations.
SuFEx Cyclization Enables DNA-Encoded Macrocyclic Peptide Libraries for Drug Discovery ↗
TwoStep Therapeutics Lands $62.5M and FDA IND Clearance for Peptide-Based ADC Alternative
- TwoStep Therapeutics, a 2024 Stanford spinout, announced an oversubscribed $62.5M Series A financing on September 10, 2026, alongside FDA clearance of the investigational new drug (IND) application for its lead candidate, TS-104.
- The round was led by Insight Partners and Medical Excellence Capital, with pharma-linked corporate venture arms M Ventures (Merck KGaA) and Pfizer Ventures co-leading; existing investors NFX, 2048 Ventures, and Stanford University also participated, bringing total funding raised to $71.2M.
- TS-104 is a first-in-class multi-specific peptide-drug conjugate (PDC) that pairs a polyspecific integrin-binding peptide, engineered to bind five tumor-associated integrins across solid tumors, with the cytotoxic payload MMAE, also used in several approved antibody-drug conjugates.
- The company positions this peptide-based platform as an alternative to antibody-based ADCs for reaching solid tumor targets.
- The IND clearance opens the way for a first-in-human Phase 1 trial, with patient enrollment expected later this year.
PDCs are pitching themselves as the cheaper, more tumor-penetrant cousin of ADCs — same MMAE payload, smaller delivery vehicle, potentially better access to solid-tumor stroma where antibodies struggle. That's a direct pitch at the ADC franchise now dominating oncology dealmaking. The investor list matters more than the dollar figure: M Ventures and Pfizer Ventures co-leading, not just writing a check, reads as two ADC-heavy pharmas hedging their own franchises and buying an early look at a modality that could either complement or cannibalize their antibody platforms. Oversubscribed Series A plus IND clearance inside two years of founding is a fast validation cycle for a still-unproven conjugate class — worth watching whether Phase 1 tolerability holds up before any partnering thesis gets real.
Exclusive: Cancer biotech TwoStep gets $62.5M to take twist on ADCs into clinic ↗
Bicyclic Peptide Libraries Deliver First Noncarbohydrate Inhibitors of the Hard-to-Drug Receptor Siglec-7
- 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.
The allosteric site is the real hook here — a bicyclic peptide binding away from the canonical glycan pocket on a target everyone assumed only the carbohydrate-recognition domain was druggable gives you a completely different SAR vector than trying to out-compete sialic acid for its own pocket. That's genuinely exciting for Siglec-7. But I'd want the nonspecific binding in the cell assays resolved before getting attached to any single lead — multivalent avidity effects can paper over a mediocre core affinity, and that's exactly the kind of artifact that kills a program downstream. Bicyclics themselves are the right chemotype to bet on: synthesizable, chemically stable enough for iterative SAR, and unlike DEL small molecules they're not fighting the flat, shallow topology that's stalled every prior GBP inhibitor effort.