Discovery of INCB159020, an Orally Bioavailable KRAS G12D Inhibitor

The inhibition of mutant KRAS proteins
has emerged as a promising
approach for treating KRAS-driven cancers, as evidenced by the clinical
success of KRAS G12C inhibitors. KRAS G12D, the most common mutant,
promises significant expansion of the addressable patient population;
however, the reduced nucleophilicity of aspartate compared to cysteine
poses significant challenges in balancing sufficient potency with
ADME properties to support oral exposure. Herein, we describe the
discovery of KRAS G12D inhibitor 23 (INCB159020), which achieves oral exposure in nonhuman primate (NHP). Starting
from a weakly potent hit, structure-based drug design was utilized
to drive significant potency. Focus on molecular rigidity and balanced
polarity then allowed for successful optimization of properties required
for oral exposure.