Seven science items, from a rescued HIV NNRTI lead and selective wild-type KIT inhibitors to covalent MAP2K4/7 targeting, OGT-recruiting chimeras, masked T cell engagers, a new hit-finding library and an oral GLP-1 review, plus Novartis's $7.8B Abogen mRNA T-cell engager license.
2026-09-30 · ⚗️OGT-recruiting bifunctional chimeras (OGTACs) · Accounts of Chemical Research (ACS)
- OGT/OGA inhibition affects thousands of substrates, so protein-specific O-GlcNAc functions are hard to assign; OGTACs address this by recruiting OGT to a chosen protein.
- Each OGTAC joins an OGT-engaging element, a linker and a target-recognition motif, and can partly bypass TPR-domain substrate recognition.
- Productive O-GlcNAc writing needs proper ternary-complex formation and noninhibitory OGT binding, while the target-recognition motif sets targetable scope and selectivity.
- Local installation is linked to changes in protein turnover, signaling and transcription.
💡 PointsThe OGT-binding warhead is the make-or-break piece here: if it inhibits OGT, you lose the very activity you're trying to redirect, so noninhibitory binders are the real SAR hurdle, much as with E3 ligands in degraders. I also like that the target-recognition motif, not OGT's TPR domain, sets selectivity, which makes this modular. It's an Accounts-level overview, so I'd want to see how well the chimeras hold up across targets before getting excited.
Chemically Induced Proximity for Targeted Protein O-GlcNAcylation ↗
2026-09-28 · ⚗️Masked bispecific T cell engagers (CD3 x PSMA/HER2 nanobody) · ACS Chemical Biology (ACS)
- Anti-CD3 Fabs (OKT3, UCHT1) are sterically masked by leucine-zipper coiled-coil domains fused through protease-cleavable linkers, and paired with PSMA- or HER2-targeting nanobodies.
- Masking strongly lowered CD3 binding, and protease cleavage restored most of it, both on recombinant CD3 and on T cell-displayed CD3.
- Masked constructs did not activate Jurkat cells, whereas unmasked ones did.
- MMP2-cleavable versions drove MMP2-dependent killing of PSMA+ and HER2+ cancer cells in PBMC co-cultures, aiming to limit on-target off-tumor toxicity.
💡 PointsThe appeal is that the mask is modular: swap the cleavable linker and the same leucine-zipper scaffold could, in principle, be retuned to a different protease, which is more flexible than hard-wiring one design. What I would press on is the gap between cleaved and unmasked binding, since 'most' restored is not full, and MMP2 is not strictly tumor-restricted. Only Jurkat and PBMC co-cultures here, so the off-tumor safety claim is still an aim, not data.
Proteolytic Activation of T Cell Engagers And Bispecific Proteins Using Modular Coiled-Coil Peptides ↗
2026-09-24 · ⚗️HIV-1 reverse transcriptase (NNRTI) · Journal of Medicinal Chemistry (ACS)
- JK-4b, a potent NNRTI active against wild-type and clinical HIV-1 variants, was shelved because of high cytotoxicity; the authors used it as a lead for new analogues.
- Structure-guided designs addressing the NNRTI entrance channel gave a series with lower cytotoxicity and improved selectivity.
- Lead compound 9n retained strong potency against common resistance mutants, including double mutants, at levels comparable to etravirine.
- 9n also showed minimal cytochrome P450 inhibition and good human liver microsome stability, supporting further development.
💡 PointsRescuing a shelved lead is always more interesting than starting cold: JK-4b already had the potency and resistance coverage, so the real question was whether entrance-channel contacts could decouple that from its cytotoxicity. If 9n's profile holds up, that suggests the toxicity was scaffold-tunable, not baked into the pharmacophore. Matching etravirine on double mutants while staying clean on P450 and microsome stability is what I'd want to see before making more.
Targeting the HIV-1 NNRTI Entrance Channel: Structure-Guided Optimization for Enhanced Safety and Selectivity ↗
2026-09-24 · ⚗️GLP-1 receptor (small-molecule agonists) · Journal of Medicinal Chemistry (ACS)
- Reviews nonpeptidic GLP-1 receptor agonists that reached the clinic, including danuglipron, lotiglipron, DA-302168S and orforglipron, as case studies of how each solved the oral-delivery problem.
- Notes the design challenges these first-generation molecules still leave open.
- Proposes next-generation approaches: peptidomimetic design, multi-target agonists, and exploiting orthosteric-allosteric cooperativity.
- Covers practical aspects such as screening cascades, preclinical species choice, formulation and early safety assessment, with relevance to other difficult GPCRs.
💡 PointsFour clinical chemotypes, four different answers to the same problem: a class B GPCR built to bind a large peptide. What I want from a review like this is the SAR logic behind each survivor. Orthosteric-allosteric cooperativity is the idea I'd chase, since it could loosen the potency-versus-permeability tradeoff. Whether it holds up depends on the screening cascade and species choice, which is where programs usually stumble.
Oral Small-Molecule GLP-1 Receptor Agonists: Lessons from Clinical Candidates and a Blueprint for Next-Generation Design ↗
2026-09-06 · ⚗️MAP2K4/MAP2K7 (JNK pathway) covalent inhibitors · ACS Chemical Biology (ACS)
- Pancreatic cancer cells that adapt to KRAS G12D inhibition can be pushed back toward sensitivity by suppressing the JNK pathway more completely.
- Selective covalent inhibitors of MAP2K4, MAP2K7, or both were used to probe how much JNK suppression is needed.
- Stronger JNK blockade disables the feedback loop that reactivates KRAS signaling in resistant cells.
- Inhibitor-sensitive cells gain no benefit, so the vulnerability is specific to the resistant state.
💡 PointsIf this holds up, the interesting part is the logic: resistance to a KRAS G12D inhibitor runs through JNK feedback, so you hit the node that rewires the pathway, not KRAS again. Covalent engagement of MAP2K4 and MAP2K7 is a neat way to ask how deep the suppression must be, though kinase selectivity between the two will be the real SAR headache. Sparing sensitive cells is the encouraging bit; it's abstract-level so far.
Exploiting Acquired Drug Resistance in Pancreatic Cancer through Selective Covalent Targeting of MAP2K4/7 ↗
2026-09-04 · ⚗️KIT (wild-type) kinase inhibitors · Journal of Medicinal Chemistry (ACS)
- Close ATP-site similarity across class III receptor tyrosine kinases makes selective KIT inhibition hard; this work tackles it with structure-guided optimization.
- A triazolopyridine hinge binder gave a selective start, and a central linker change led to a reverse arylacetamide series with better potency and pharmacokinetics.
- A pyrazole linker and hinge-motif edits kept potency in human serum, while terminal aryl tuning reduced CYP time-dependent inhibition and sharpened kinome selectivity.
- Crystal structures showed that linker stereoelectronics near the gatekeeper can drive selectivity, yielding a lead suited to chronic therapy.
💡 PointsThe linker, not the hinge binder, is what caught my eye: stereoelectronics near the gatekeeper apparently buy selectivity that ATP-site similarity across class III RTKs would otherwise deny. That is a handle worth stealing for other crowded kinase families. I also like that CYP time-dependent inhibition and human-serum potency were fixed in the same campaign, which reads like a lead meant for chronic dosing.
Leveraging Structure-Based Design to Overcome Class III RTK Off-Target Activity in the Development of Selective Wild-Type KIT Inhibitors ↗