FT385 is a covalent inhibitor of the USP30 deubiquitinating enzyme with a cyanopyrrolidine warhead. Identifying selective active-site inhibitors of de-ubiquitinating enzymes has been challenging, and FT385 now provides a good tool compound to study USP30 biology. Some of my colleagues at Genentech recently published on the mechanism of [...]

BridgeBio’s BBO-8520 is a selective, covalent KRAS(G12C) inhibitor which differentiates itself from the pack by engaging the (ON) state of the protein, potentially conferring increased clinical benefit in KRAS(G12C)-driven cancers, including overcoming resistance to current treatments. Disclosed at the 2024 AACR Annual Meeting in San Diego, is currently in a Ph. I trial in patients with advanced non-small-cell lung cancer. This article covers the structure, mechanism of action and preclinical efficacy that marks this compound out as one to watch.

The FGFR family of receptors are well-validated targets in cancer. While specific FGFRs like FGFR2 can drive cancers like cholangiocarcinoma, broad inhibition of FGFRs leads to significant off-target toxicities. Relay Therapeutics captured industry attention when they announced the discovery of an FGFR2 isoform-selective inhibitor, lirafugratinib, using a molecular dynamics simulations approach. This article provides an overview of the pan-FGFR landscape, explores the specifics of the FGFR2 selectivity, preclinical pharmacology, and early clinical data for this remarkable molecule.

Pfizer’s PF-07321332 (API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which received emergency use authorization from the FDA for Covid treatment at the end of 2021. Clinical data showed Paxlovid reducing Covid hospitalization and death by 89%. It was nominated for November’s cover by Mike Koehler [...]

VVD-214/RO7589831 is an oral covalent, reversible, and allosteric inhibitor of WRN helicase discovered by the San Diego-based biotech Vividion Therapeutics and being developed by Roche for tumors marked by microsatellite instability and/or mismatch repair deficiency. Vividion has utilized its chemoproteomics platform to discover and develop novel treatment options for oncology targets. The structure and initial preclinical pharmacology data for VVD-214 were recently disclosed at the AACR Annual Meeting 2024 in San Diego. VVD-214 is currently being evaluated in a Ph. I trial.