Abstract 6258: The discovery and preclinical characterization of the potent covalent KRASG12C inhibitor UCT-001024

Abstract

Abstract Small molecule inhibitors of KRASG12C have garnered substantial interest as a targeted therapy for lung, colon and pancreatic cancers bearing this mutation. Data from multiple clinical programs have shown strong efficacy in lung tumors but diminished and differential efficacy for other tumor sites including lung-derived brain metastases. We undertook a series of in vitro and in vivo studies to evaluate clinically staged KRASG12C inhibitors in an effort to elucidate pharmacological factors underlying these clinical differences and identified potency, permeability/efflux, and clearance as impediments to efficacy, particularly in the context of brain metastases. Adagrasib is reportedly efficacious in patients with brain metastases. Our preclinical experimentation suggests that distinguished potency and pharmacokinetics are critical to therapeutic benefit, particularly in the context of brain metastases. Using both structure- and ligand-based design approaches, we identified a development candidate UCT-001024, which is a covalent KRASG12C inhibitor that demonstrates superior target-engagement kinetics and cellular potency in vitro. UCT-001024 also demonstrates improved plasma and whole brain unbound clearance, and in vivo potency in ectopic xenograft models and a brain-tropic NSCLC metastasis model relative to adagrasib. Additionally, UCT-001024 shows a favorable DDI profile and ion channel safety in an in vitro iPSC-derived cardiomyocyte cardiac proarrhythmia assay. Citation Format: Tristin E. Rose, Brendan M. O'Boyle, Justin A. Hilf, Emma L. Baker-Tripp, Zhengao Feng, Kevin Yang, Michael D. Bartberger, Oliver C. Losón, Neil A. O'Brien, Martina S. McDermott, Naeimeh Kamranpour, Weiping Jia, Tong Luo, Raul Ayala, John Glasby, Brian M. Stoltz, Dennis J. Slamon. The discovery and preclinical characterization of the potent covalent KRASG12C inhibitor UCT-001024 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6258.