molecules of the month

A CNS-Penetrant KRASG12C Inhibitor Intended for CNS-Metastatic Cancers AZD4747 is a CNS-penetrant, oral KRASG12C covalent inhibitor for the treatment of CNS-metastatic KRAS-mutant cancers. KRAS inhibitors have tended to be quite large and fall outside the range of physicochemical properties generally required for CNS permeability (MW < 360 Da, cLogD < 2, TPSA < 90 Å2). AZD4747 is much smaller than marketed KRASG12C inhibitors but maintains exceptional cellular potency. Unlike adagrasib, AZD4747 does not have a basic amine, has a low PSA and a low MDCK efflux ratio, and can therefore achieve brain penetration without relying on other mechanisms, such as the P-gp inhibition speculated by Mirati. The team also encountered an unexpected toxicity that scientists working on covalents should pay…