A Structurally Distinct MTA-Cooperative PRMT5 Inhibitor With a “Fantastic Fluorine Atom” | https://lnkd.in/gPuNpsgD AZ-PRMT5i-1 is an orally bioavailable MTA-cooperative PRMT5 inhibitor that specifically targets MTAP-deleted cancers and is structurally related to AstraZeneca's clinical candidate, AZ3470. Selectively targeting PRMT5 in MTAP-deleted cancers has been an incredibly competitive space lately, which is notable given that PRMT5 was once considered a failed target after first-generation inhibitors displayed intolerable on-target toxicities. With an improved understanding of target biology and synthetic lethality, the interest in the target has been revived. This case study is an excellent example of utilizing bioisosteric replacements for polar guanidine headgroups, rigidifying scaffolds through spirocyclization to reduce rotatable bonds, and leveraging fluorine atoms beyond simply blocking metabolic soft spots. Full Article: https://lnkd.in/gPuNpsgD
Principal Research Analyst, Drug Discovery
4 天前Yay! My first Drug Hunter post! Many people at Drug Hunter helped me with this. I want to thank especially Rory McAtee, Dennis Koester, Lew Pennington and Jennifer Huen for their contributions. See my brief personal description of the work here: https://www.dhirubhai.net/feed/update/urn:li:activity:7264797064813768704/