143D, a novel selective KRAS inhibitor exhibits potent antitumor activity in preclinical models.

The KRAS mutant has emerged as an important therapeutic target in recent years. Covalent inhibitors have shown promising antitumor activity against KRAS-mutant cancers in the clinic. In this study, a structure-based and focused chemical library analysis was performed, which led to the identification of 143D as a novel, highly potent and selective KRAS inhibitor. The antitumor efficacy of 143D in vitro and in vivo was comparable with that of AMG510 and of MRTX849, two well-characterized KRAS inhibitors. At low nanomolar concentrations, 143D showed biochemical and cellular potency for inhibiting the effects of the KRAS mutation. 143D selectively inhibited cell proliferation and induced G-phase cell cycle arrest and apoptosis by downregulating KRAS-dependent signal transduction. Compared with MRTX849, 143D exhibited a longer half-life and higher maximum concentration (C) and area under the curve (AUC) values in mouse models, as determined by tissue distribution assays. Additionally, 143D crossed the blood‒brain barrier. Treatment with 143D led to the sustained inhibition of KRAS signaling and tumor regression in KRAS-mutant tumors. Moreover, 143D combined with EGFR/MEK/ERK signaling inhibitors showed enhanced antitumor activity both in vitro and in vivo. Taken together, our findings indicate that 143D may be a promising drug candidate with favorable pharmaceutical properties for the treatment of cancers harboring the KRAS mutation.