Abstract 4044: Development of UCT-01-097, a novel orally available ERK1/2 inhibitor for the treatment of ERK1/2 dependent cancers

Abstract The MAPK signaling pathway is the most commonly mutated and/or dysregulated pathway in cancer. Strategies to target it have yielded some success with inhibitors against KRASG12C and BRAF, and to a lesser extent, MEK1/2. However, the impact of these molecules is often limited by toxicity and rapid and diverse mechanisms of resistance; both adaptive and/or acquired. For example, treatment with MAPK pathway targeting agents results in compensatory activation of the downstream mediator ERK1/2 and enables tumors to subvert the targeted therapy. Thus, targeting ERK1/2 provides promising potential advantages in overcoming and/or preventing adaptive and acquired resistance. We evaluated multiple preclinical and clinically staged ERK1/2 inhibitors—including ERAS-007 and BVD-523—in a 500+ cell line screening platform and identified cancers with subpopulations that are sensitive to this class of inhibitor. KiNativ analyses helped to inform the differences in sensitivity/selectivity that we observed between each ERK1/2 inhibitor. Comprehensive molecular profiling of the cell lines at baseline allowed us to screen for potential molecular markers of sensitivity/resistance to these compounds. Using this platform, we have developed a novel, potent ERK1/2 small molecule inhibitor, UCT-01-097, with improved selectivity over other clinically staged inhibitors. These data, coupled with the broad spectrum of in vitro responses, suggests an improved therapeutic index with this molecule. UCT-01-097 shows kinase selectivity in both cell free and in-cell assays and robust efficacy in panel of pancreatic PDX models. Inhibition of xenograft tumor growth was achieved using both daily dosing and intermittent dosing schedules. We have successfully submitted a regulatory IND and are currently enrolling a Phase 1 clinical trial in advanced solid tumors for treatment with UCT-01-097 (NCT04761601). Citation Format: Neil A. O'Brien, Martina S. McDermott, Brendan M. O'Boyle, Corey M. Reeves, Michael Bartberger, Oliver Loson, Kevin Chau, Jenny J. Hong, Weiping Jia, Naeimeh Kamranpour, Tong Luo, Raul Ayala, Athena M. Madrid, John A. Glaspy, Brian M. Stoltz, Dennis J. Slamon. Development of UCT-01-097, a novel orally available ERK1/2 inhibitor for the treatment of ERK1/2 dependent cancers. [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 4044.