AZD4747 is a CNS-penetrant, oral KRAS G12C 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 KRAS G12C inhibitors but maintains exceptional cellular potency. The team also encountered an unexpected toxicity that scientists working on covalents should pay attention to. PET brain penetration data for AZD4747, adagrasib, and sotorasib across species are also summarized here.