Five science items today: a macrocycle-derived EGFR PROTAC, two PKMYT1/OGG1 chemotypes, HIPK4 cyanoquinolines for male contraception and an NLRP3 inhibitor for colitis. Business: Genentech's $100M AL050 deal, Merck's KRAS G12D license and Lycia's LYTAC IPO filing.
2026-10-05 · ⚗️EGFR PROTAC (C797S-resistant NSCLC) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsStarting 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.
Development of Potent and Selective EGFR-PROTACs Based on Macrocyclic Fourth-Generation EGFR Inhibitors ↗
2026-10-05 · ⚗️HIPK4 inhibitors (non-hormonal male contraception) · Journal of the American Chemical Society (ACS)
- HIPK4 is a spermatid-specific kinase needed for sperm head shaping, making it a candidate non-hormonal contraceptive target.
- A cyanoquinoline series gave potent, HIPK4-selective inhibitors, selective within the HIPK family and across the kinome.
- Some compounds also altered HIPK4 proteostasis in spermatids, causing insoluble aggregates and recruiting the autophagy receptor TAX1BP1.
💡 PointsA selective kinome-wide profile from a first series is what a probe needs, and the unexpected proteostasis effect is the intriguing bit: it hints at a degrader-like mode that could be tuned. For contraception the bar is brutal, though, with reversibility and long-term safety to prove.
Small-Molecule Modulators of HIPK4 Activity and Proteostasis ↗
2026-10-05 · ⚗️OGG1 catalytic activators (ORCAs) · Journal of Medicinal Chemistry (ACS)
- Most OGG1 work has aimed at inhibitors; these mitochondria-enriched ORCAs instead reprogram the enzyme's catalysis.
- Biochemistry, mutagenesis and X-ray crystallography showed active-site binding that favors beta-elimination over glycosylase turnover.
- ORCAs protected mitochondrial function under oxidative stress, raised NAD levels in cortical neurons and were neuroprotective in a retina axotomy model.
💡 PointsActivating rather than inhibiting an enzyme is rare and hard to do, so a crystal structure showing the mechanism is what makes this credible. The open question is long-term safety: pushing a repair enzyme to a different catalytic outcome could create unusual DNA lesions, and the neuroprotection data are still early.
Development of Organocatalytic Switches of OGG1 that Protect Mitochondria under Oxidative Stress ↗
2026-10-05 · ⚗️PKMYT1 inhibitors (CCNE1-amplified cancers) · Journal of Medicinal Chemistry (ACS)
- A hydrogen-bond donor-to-acceptor conversion was used to lower the donor count of a 4-aminoquinazoline PKMYT1 series and improve drug-likeness.
- Lead 12f was a nanomolar enzyme inhibitor, potent in OVCAR-3 ovarian cells and synergistic with PARP inhibitors.
- With acceptable oral PK, it showed efficacy in an OVCAR-3 xenograft and was well tolerated.
💡 PointsTrimming HBDs is a clean, transferable tactic for improving permeability and oral exposure in a kinase series. The PARP-inhibitor synergy is the commercially interesting part, but PKMYT1 is crowded, so I'd check selectivity against other kinases and how 12f compares with the clinical frontrunners.
Discovery of 4-Aminoquinazoline Derivatives as Potent PKMYT1 Inhibitors via Hydrogen Bond Donor-To-Acceptor Conversion for CCNE1-Amplified Cancers ↗
2026-10-04 · ⚗️NLRP3 inflammasome inhibitors · Journal of Medicinal Chemistry (ACS)
- The anti-Parkinsonian drug istradefylline showed modest NLRP3 inhibition, and optimizing it gave a thienopyrimidinone series.
- Lead L22 was roughly tenfold more potent than istradefylline, bound the NLRP3 NACHT domain directly and blocked inflammasome assembly.
- It was orally bioavailable, eased symptoms in a DSS colitis model and looked safe in acute and subacute toxicity studies.
💡 PointsStarting from a marketed drug's off-target activity gives a head start on drug-likeness, and direct NACHT-domain binding is what you want to see. NLRP3 is a busy field, so the real test is how L22 compares with clinical-stage inhibitors on potency and brain or gut exposure.
Design, Synthesis, and Anti-Inflammatory Activity Evaluation of Novel thieno[2,3-d]Pyrimidin-4(3H)-One-Based NLRP3 Inflammasome Inhibitors ↗
2026-10-06 · 🏢IPO filing · Endpoints News · Lycia Therapeutics
- Lycia Therapeutics filed publicly for an IPO of up to $100M on Nasdaq under LYCA, after a confidential filing in July.
- Its LYTAC platform, from Carolyn Bertozzi's lab, shuttles extracellular proteins to the lysosome for degradation.
- Lead LCA-0061 degrades IgE for food allergy and is in Phase 1; LCA-0321 targets Graves' disease autoantibodies.
💡 PointsEarly healthy-volunteer data showing a deep IgE drop give the story a clinical anchor, and an IPO is a useful test of public-market appetite for degraders outside oncology. The competition is formidable, though: omalizumab and its successors already own IgE, so Lycia must show a durable, differentiated edge.
Lycia seeks IPO for antibody degraders as TRexBio, Retension set terms ↗
2026-10-05 · 🏢Licensing deal · Fierce Biotech · Genentech / Alector
- Alector licensed AL050, a preclinical brain-penetrant engineered GCase enzyme replacement therapy for Parkinson's disease, to Genentech.
- The deal brings $100M upfront, up to $1.17B in milestones and tiered royalties; Genentech takes development, manufacturing and commercialization.
- Alector keeps its Brain Carrier platform, and the cash extends its runway into 2029.
💡 PointsA $100M upfront for a preclinical asset shows how much Roche values a validated blood-brain barrier shuttle in GBA1-linked Parkinson's. For Alector, it's a lifeline that funds its Alzheimer's and siRNA programs. The risk is that delivery, not the enzyme, is the real bet, and Genentech has other shuttle options.
Genentech pays Alector $100M for preclinical Parkinson's prospect ↗
2026-09-28 · 🏢Licensing deal · Endpoints News · Merck / SciBrunch Therapeutics
- Merck took exclusive worldwide rights to SPR2015, an oral preclinical KRAS G12D (ON) inhibitor from Shanghai-based SciBrunch.
- SciBrunch gets $400M upfront, with total potential value of $2.13B across milestones.
- The deal has already closed.
💡 Points$400M upfront for a preclinical asset is striking and shows how heated the KRAS G12D race has become, with China-originated assets now priced like clinical ones. For Merck it's a late entry into a field where it needs a differentiated ON-state profile, and the one to watch is first-in-human data.
Merck licenses a KRAS G12D inhibitor for $400M upfront ↗