65 (PB055) - Discovery and characterization of ABSK071, a novel and potent small-molecule covalent inhibitor for KRAS-G12C

Abstract

KRAS is frequently mutated in human cancers, including pancreatic (∼90%), colorectal (∼35%), and lung cancer (∼25%). The KRASG12C mutation (single amino acid substitution of cysteine for glycine at position 12) accounts for ∼14% of lung cancer, ∼4% of colorectal cancer, and ∼2% of pancreatic cancer. Recently, covalent inhibitors such as sotorasib have been designed to target the mutated cysteine in codon 12 and have achieved clinical benefit for these patients. Here, we describe the discovery and characterization of ABSK071, a novel and highly potent small-molecule inhibitor that irreversibly modifies and inhibits KRASG12C in vitro and in vivo. In cellular experiments, ABSK071 treatment inhibited KRAS signaling across a panel of KRASG12C mutant cancer cell lines, as measured by the phosphorylation of ERK1/2 (p-ERK). The treatment of ABSK071 resulted in significantly impaired cell viability at nanomolar concentration, which is superior to the approved KRASG12C inhibitor sotorasib. Further, in vivo pharmacodynamic study demonstrated the dose- and time-dependent inhibition of KRAS signaling by ABSK071. in vivo efficacy studies showed that ABSK071 has higher antitumor potency than sotorasib at the same dose in multiple xenograft models. Together, these data demonstrated the antitumor activity of ABSK071 towards KRASG12C-dependent cancers. Conflict of interest: Ownership: All co-authors are stock owners of Abbisko Therapeutics.