Covalent Fragment Screening with Chemoproteomics: KEAP1 Engagers with an Unusual Warhead

KIN-3248 (Kinnate Biopharma) is a next-generation, irreversible, pan-fibroblast growth factor receptor inhibitor (FGFRi) in a first-in-human (FIH) dose-escalation study (NCT05242822) in adults with advanced tumors harboring FGFR2 and FGFR3 gene alterations. The program is an excellent case study for rational covalent drug design to address kinase mutations while maintaining sufficient PK properties for oral daily dosing in humans.

PF-07817883 (ibuzatrelvir) is an oral, second-generation SARS-CoV-2 M^pro inhibitor developed by Pfizer. These efforts follow the success of Pfizer's antiviral combination drug, Paxlovid, which was granted Emergency Use Authorization by the FDA for the treatment of COVID-19. PF-07817883 was granted Fast Track designation and recently completed a Ph. II clinical trial in outpatient adults with COVID-19 symptoms. This article details the discovery strategy for PF-07817883, which includes addressing metabolic soft spots identified through MetID studies, recent clinical developments, and more.

In Wednesday’s Flash Talk webinar, we covered recent highlights in covalent drug discovery, with lots of great questions from the audience. The webinar and recording are available below to everyone thanks to our sponsor, Revvity Signals, and the slides are available for download to Premium members at the bottom.

On Feb. 16, 12:00PM PST, Dr. Mira Pochon, Staff Scientist and Head of Translational Biology at Global Blood Therapeutics, gave a PBSS/CLSA webinar on one of 2019's drug approvals , voxelotor (GBT440).  Mira has been with GBT since it’s early days in 2011.  GBT’s chemistry team was led by their CSO Dr. Brian Metcalf, former head of drug [...]

Futibatinib (Lytgobi) is a rare alkyne-containing, irreversible FGFR1-4 inhibitor that received accelerated approval from the FDA in September 2022. Structurally distinct from other approved FGFR2/3 inhibitors, futibatinib treats a range of FGFR-aberrant tumors, including those with fusions or TKI-resistant mutants like the V565I/L gatekeeper [...]