Discovery of AZD4625, a Covalent Allosteric Inhibitor of the MutantGTPase KRAS^G12C

KRAS is an archetypal high-value intractableoncology drug target. The glycine to cysteine mutation at codon12 represents an Achilles heel that has now rendered thisimportant GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of21,AZD4625, a clinical development candidate for the treatment ofKRASG12Cpositive tumors. Highlights include a quinazolinetethering strategy to lock out a bio-relevant binding conformationand an optimization strategy focused on the reduction ofextrahepatic clearance mechanisms seen in preclinical species.Crystallographic analysis was also key in helping to rationalizeunusual structure-activity relationship in terms of ring size andenantio-preference. AZD4625 is a highly potent and selectiveinhibitor of KRASG12Cwith an anticipated low clearance and high oral bioavailability profile in humans