Five science items today: PROTAC target engagement reinterpreted through intracellular exposure, a CNS-penetrant PARP1-selective inhibitor, covalent epoxysuccinate PLpro inhibitors, an AlphaLISA screen for ISG15–UBA7, and kinase-inhibitor protonation states. Business: Gilead's oral UC data and Merck KGaA buying Silence.
2026-10-18 · ⚗️SARS-CoV-2 papain-like protease (covalent) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsA potent warhead that dies in the liver is a familiar story, and here the culprit is the very linker the chemistry needs for Cys-111 reach. I'd still keep the epoxysuccinamide in the toolbox for the next coronavirus, but the linker would be the first thing I'd redesign.
Discovery of Epoxysuccinates as Potent Covalent Inhibitors of SARS-CoV-2 Papain-like Protease ↗
2026-10-17 · ⚗️PARP1-selective inhibitors (CNS-penetrant) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsSwapping the primary carboxamide is a bold move, since that group anchors the nicotinamide pocket, and the heterocycles evidently kept the binding. The more useful lesson is the filter: if Caco-2 efflux predicts unbound brain exposure better than MDR1-MDCK, plenty of CNS programs may be discarding good compounds.
Discovery of Potent, Orally Bioavailable, and CNS-Penetrant 1,2,3-Triazolopyridinyl Piperazine-Based PARP1-Selective Inhibitors ↗
2026-10-17 · ⚗️PROTACs / cereblon and VHL engagement · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsBefore I read a PROTAC SAR table as E3 affinity, I'd now ask what the cell actually saw. If most of the shift is unbound exposure, linker tweaks that look like potency gains may just be permeability gains, and measuring exposure early keeps us from chasing the wrong variable.
Exploring the Relationship between Cell Permeability, Intracellular Exposure, and Target Engagement for PROTACs ↗
2026-10-16 · ⚗️ISG15–UBA7 interaction (ISGylation) · ACS Medicinal Chemistry Letters (ACS)
- 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.
💡 PointsThis is a pilot on under a thousand compounds, so the hits are starting points, not leads. What matters is that a protein-protein interaction between a ubiquitin-like modifier and its E1 now has a screenable format. I'd run it against a real diversity set and counter-screen AlphaLISA interferers hard.
A High-Throughput Screening Platform for the Discovery of Noncovalent Inhibitors of the ISG15–UBA7 Interaction ↗