Six science items today: a selective ULK1 PROTAC, a clinical-grade PERK inhibitor, an inhaled sGC stimulator, oral POLQ inhibitors, a docking-vs-crystal-structure study and sulfonium echinocandins. Business: Roche's molecular glue deal, Merck's Keytruda SC court setback and Forbion's $2.6B fund.
2026-10-07 · ⚗️Structure-based pose prediction (SARS-CoV-2 Mpro) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsThis gives structural biology a concrete budget line: after about five structures per scaffold, the next soak buys little for pose prediction. Caveat: Mpro is a rigid, well-behaved pocket, so I'd not carry that number over to flexible kinases or induced-fit targets.
How Many Crystal Structures Do You Need to Trust Your Docking Results? ↗
2026-10-07 · ⚗️Soluble guanylate cyclase (inhaled stimulator) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsDesigning for high clearance and low permeability on purpose is the opposite of oral-drug instinct, which is exactly why this paper is useful for inhaled programs. Residence time plus lung retention is the combination I'd want to see replicated before believing the therapeutic window in humans.
Frespaciguat (MK-5475): A Novel Inhaled Soluble Guanylate Cyclase Stimulator for Pulmonary Hypertension Associated with COPD ↗
2026-10-07 · ⚗️PERK (integrated stress response kinase) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsLetting LLE drive the SAR instead of chasing potency is the discipline that makes this readable, and the alpha-fluoro benzamide trick for dodging efflux is a handy one for my own amide series. PERK's ISR biology has bitten inhibitors before, so the tolerability data will matter more than the PK table.
Discovery of a Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) Inhibitor Suitable for Clinical Progression ↗
2026-10-07 · ⚗️DNA polymerase theta (POLQ) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsA polymerase-domain inhibitor that is both oral and selective for the HR-deficient setting is what this target has been missing. The HR-proficient null result is the key control, so I'd now look at resistance and how it stacks against the helicase-domain approaches.
Discovery of a Novel Series of Benzimidazoles/Purines as Potent, Selective and Orally Active Inhibitors of the DNA Polymerase Activity of POLQ ↗
2026-10-07 · ⚗️Fungal glucan synthase (echinocandin derivatives) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsEchinocandins have never covered Cryptococcus, so adding a membrane-active cationic handle to restore activity is a smart reuse of a validated scaffold. The risk is that membrane disruption narrows the selectivity window, so host-cell toxicity data and the mechanism split deserve a close read.
Sulfonium Modification of Echinocandins: An Effective Strategy to Combat Intrinsically Resistant Cryptococcus via Membrane Disruption and Enhanced Cell Wall Biosynthesis Inhibition ↗
2026-10-07 · ⚗️ULK1 (cereblon-recruiting PROTAC) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsSelectivity between paralogs is where degraders can beat occupancy-driven drugs, and this is a clean example. What I'd check next is whether ULK2 compensation shows up in vivo, and whether washout durability holds in a model with realistic drug exposure rather than a pulse.
Discovery and Optimization of Isoform Selective ULK1 Degraders to Enhance Antitumor Activity in KRAS-Mutant Cancer ↗
2026-10-08 · 🏢Partnership / discovery deal · STAT News · Roche / Defand Therapeutics
- STAT reports Roche has signed a drug discovery deal with Chinese biotech Defand Therapeutics focused on molecular glue medicines.
- Only the public lede of the STAT+ article could be read, so financial terms and targets are unverified here.
💡 PointsRoche keeps adding molecular glue partners rather than betting on one platform, and sourcing from Chinese biotechs fits the wider licensing trend. Without upfront and milestone figures I'd treat this as a discovery-stage option play, with the real signal being which targets and how many are named.
STAT+: Roche inks drug discovery deal with Chinese biotech, focused on molecular glue medicines ↗
2026-10-07 · 🏢Financing / venture fundraise · STAT News · Forbion
- STAT reports European venture firm Forbion has raised $2.6 billion, its largest fundraise to date.
- It is described as one of the largest in the region in recent years; fund structure and allocation were not visible in the public lede.
💡 PointsA raise this size from a specialist investor says LPs still back biotech formation despite a choppy funding climate, and it gives European startups a deeper home-market option. The things to watch are the split between early-stage company creation and later rounds, and whether it pulls US-bound founders toward European listings.
STAT+: Forbion raises $2.6 billion, its largest fundraise to date ↗
2026-10-07 · 🏢Litigation / legal setback · STAT News · Merck
- STAT reports a Dutch court ordered Merck to stop manufacturing and marketing its subcutaneous Keytruda formulation in several European countries.
- Only the public lede was readable, so the plaintiff, grounds and scope are unverified here.
💡 PointsSubcutaneous Keytruda is Merck's main defense against the coming pembrolizumab biosimilar era, so any European delay hits that lifecycle plan directly. How long the order lasts and whether it is overturned on appeal matters more than the headline, and the case echoes the broader fight over SC hyaluronidase formulation patents.
STAT+: Merck suffers a setback in Europe over its new Keytruda formulation ↗