Preclinical characterization of ABSK211: A highly potent, orally bioavailable and selective pan-KRAS inhibitor with broad and robust activity in KRAS-driven tumors

KRAS is frequently mutated in human cancers, including pancreatic (~90%), colorectal (~35%), and lung cancers (~25%). Several selective pan-KRAS inhibitors have advanced into clinic but their potency against KRAS mutations remained to be further improved. Here we describe that ABSK211, discovered by Abbisko, is a highly potent, and orally bioavailable small-molecule inhibitor with broad activities against multiple KRAS mutations. ABSK211 exhibited strong target engagement in vitro against a range of KRAS mutations. Treatment with ABSK211 effectively impaired cell viability at sub-nanomolar to nanomolar concentrations across a diverse panel of cancer cell lines with different KRAS alterations, including G12 mutation, G13 mutation, Q61 mutation and WT amplification. Meanwhile ABSK211 displayed marginal inhibition in normal cell proliferation. In vivo daily oral dose of ABSK211 induced deep tumor regression in several KRAS G12V CDX models across different human cancer types. Strong target engagement in vivo was also observed. Additionally, ABSK211 exhibited robust anti-tumor activity in xenograft models with other KRAS mutations, such as KRAS G12D/S and KRAS G13D. ABSK211 is currently undergoing IND-enabling studies; its superior preclinical profile supports its advancement into clinical studies.