Abstract LB242: Discovery and characterization of BRSD-143, an orally bioavailable panKRAS inhibitor
Authors: Charles Y. Cho, Qian Liu, Jun Liu, Deborah A. Knee, David P. Kodack, Dean P. Phillips, Phillip B. Alper, Hong Jin, Wendy Richmond, Sarah E. Kochanek, Hong Yin, Yu Chen, Jie Li, Cyrus Virata, David H. Jones, Jose C. Juarez, Michael DiDonato, Brandon L. Taylor, Dmitry Borkin, Dong Han, Xianzhong Liu, Vicki W. Zhou, Lilin Li, Rita Das, Varunika Vivekanandan, Flavio Somanji, David A. Ruddy, Michelle Piquet, Miriam Coor, Eiru Kim, Yelena Sarkisova, Min Lu, Guoxun Liu, Danielle Roman, William P. Gordon, Todd Groessl, Michael Shapiro, Yvonne Wang, Darbi Witmer, Agnes Vidal-Biggart, Yong Jia, Jacob R. Haling
Journal: Cancer Research (2025)

Abstract KRAS is frequently mutated in lung, pancreatic and colorectal cancers. Discovery of the Switch II (SwII) pocket, development of covalent KRAS G12C inhibitors, and FDA approval of KRAS targeting drugs have transformed the treatment landscape and possibilities for these difficult to treat cancers. However, there is still high unmet medical need in tumors harboring KRAS mutations outside of KRAS G12C, for which no targeted KRAS therapy has been approved. Here, we present preclinical data on BRSD-143, a potent inhibitor of multiple KRAS mutants. To identify starting points for a panKRAS inhibitor, we screened a library of proprietary and literature compounds for binding to 28 RAS proteins, covering a range of KRAS mutants and wild-type KRAS/HRAS/NRAS in both GDP and GMPPNP-bound states. The hit molecules were optimized to yield BRSD-143, a highly potent panKRAS inhibitor. BRSD-143 bound to KRAS wt, G12D, and G12V with low picomolar affinity. BRSD-143 was tested for inhibition of MAPK signaling in 15 cell lines (KRAS G12D, G12V, G12C, G12A, G12S, G13D, Q61H, and wt amp), and inhibited pERK with low to sub-nanomolar activity (0.3 - 3.1 nM). Efficacy was evaluated in six cell derived xenograft models spanning KRAS G12V, G12D, and wt amplification covering lung, colorectal, pancreatic, gastric, and leiomyosarcoma cancers. In a head-to-head study, BRSD-143 had comparable anti-tumor activity to a panRAS inhibitor and an allele-specific KRAS G12D inhibitor in the SW1990 tumor model. Further, BRSD-143 caused regression of KRAS G12D mutant CT26 mouse tumors in immunocompetent hosts. BRSD-143 treatment increased T cell infiltration, M1 macrophage polarization, and CD11b+ dendritic cell infiltration into CT26 tumors. BRSD-143 was also found to synergize with known drugs such as EGFR, PI3K, YAP/TEAD, BCL-XL, panBET inhibitors, and others. In conclusion, BRSD-143 is a highly potent panKRAS inhibitor that has efficacy across a range of cell derived xenograft models. In this study, direct comparison of panKRAS, panRAS, and KRAS G12D specific inhibitors suggested equivalent efficacy can be achieved by these different mechanisms. However, further studies are necessary to understand effects on the anti-tumor immune response and which compounds can be best combined with KRAS targeting inhibitors. Citation Format: Charles Y. Cho, Qian Liu, Jun Liu, Deborah A. Knee, David P. Kodack, Dean P. Phillips, Phillip B. Alper, Hong Jin, Wendy Richmond, Sarah E. Kochanek, Hong Yin, Yu Chen, Jie Li, Cyrus Virata, David H. Jones, Jose C. Juarez, Michael DiDonato, Brandon L. Taylor, Dmitry Borkin, Dong Han, Xianzhong Liu, Vicki W. Zhou, Lilin Li, Rita Das, Varunika Vivekanandan, Flavio Somanji, David A. Ruddy, Michelle Piquet, Miriam Coor, Eiru Kim, Yelena Sarkisova, Min Lu, Guoxun Liu, Danielle Roman, William P. Gordon, Todd Groessl, Michael Shapiro, Yvonne Wang, Darbi Witmer, Agnes Vidal-Biggart, Yong Jia, Jacob R. Haling. Discovery and characterization of BRSD-143, an orally bioavailable panKRAS inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB242.