ZE98-0277

ZE98-0277 is a potent, highly selective, and orally bioavailable small molecule non-covalent inhibitor of the KRAS[G12D] oncogenic mutation. KRAS[G12D] is a major driver in several high-prevalence cancers, including approximately 35% of pancreatic, 13% of colorectal, and 4% of non-small cell lung cancers. Unlike covalent inhibitors that target the cysteine residue in G12C mutations, ZE98-0277 employs a non-covalent mechanism to inhibit the aspartic acid mutant (G12D). Preclinical evaluations have shown an IC50 of 6.3 nM in KRAS[G12D] mutant cell lines and significant efficacy in mouse xenograft models. The drug candidate exhibits favorable ADME properties, including 20-40% oral bioavailability in mice and monkeys, and a broad therapeutic window (>100x). It is currently being developed for the treatment of KRAS[G12D] mutant tumors.