Discovery of INCB161734: A Selective Inhibitor of the KRAS G12D Mutant

The discovery of the clinical KRAS G12D inhibitor INCB161734 is described. Starting from a previously disclosed orally bioavailable tool compound 1, a concerted effort to improve the predicted human dose via modulation of potency and pharmacokinetics was undertaken. Careful consideration of the metabolic profile was key to designing low clearance compounds. In addition, the molecular size and fraction sp3 character were carefully controlled to improve permeability and crystalline solubility. From this effort, INCB161734 was identified as a balanced compound with excellent oral exposure, potent antiproliferative activity in xenograft tumor models, and excellent selectivity against wild-type K/H/NRAS. INCB161734 is currently undergoing clinical trials in patients with KRAS G12D mutations.