Discovery and preclinical evaluation of a potent, orally bioavailable, highly selective, small molecule non-covalent KRAS[G12D] inhibitor

KRAS[G12D] oncogenic mutation is present in ~35% of pancreatic, 13% of colorectal, and 4% of non-small cell lung cancers. The mutation also occurs in other cancer types, albeit less frequently. Here we would like to present compelling evidences that ZE98-0277 has potent and selective activity in KRAS[G12D] mutant cell lines and in vivo models. ZE98-0277 drug candidate demonstrates strong in vitro activity (IC50 KRAS[G12D] 6.3 nM) and oral PK, bioavailability ~20-40% in mice and monkeys, broad therapeutic window (>100x in cellular models), good safety and tolerability, favorable ADME properties (solubility, stability, permeability, low hERG inhibition, minimal off-target effects), effective tumor suppression in multiple mouse xenograft models. These preclinical results demonstrate that ZE98-0277 is a potent, selective, and orally bioavailable KRAS[G12D] inhibitor, strongly efficacious against KRAS[G12D] mutant tumors slated for further development.