Abstract 1261: A next generation tri-complex KRASG12C(ON) inhibitor directly targets the active, GTP-bound state of mutant RAS and may overcome resistance to KRASG12C(OFF) inhibition
Authors: Robert J. Nichols, Jim Cregg, Christopher J. Schulze, Zhican Wang, Kevin Yang, Jingjing Jiang, Daniel M. Whalen, Rich Hansen, Lindsay S. Garrenton, Alun Bermingham, John E. Knox, Tiffany Choy, Denise Reyes, Mayra Rios, Kyle Seamon, Michael Longhi, Kang-Jye Chou, Shaoling Li, David P. Wildes, Mallika Singh, Elena S. Koltun, Adrian L. Gill, Jacqueline A. M. Smith
Journal: Cancer Research (2021)

Abstract The KRASG12C mutation is found in 11% of non-small cell lung cancers and 4% of colorectal cancers. Recently, a class of KRASG12C(OFF) inhibitors has shown promising activity in patients whose cancers bear KRASG12C. These data validate KRASG12C as an oncogenic driver, as well the mechanism of action of the KRASG12C(OFF) inhibitor class – sequestration of inactive, GDP-bound KRASG12C(OFF) proteins. Previous work has demonstrated this mechanism of action is vulnerable to adaptive tumor cell responses that activate KRASG12C by increasing upstream signaling and driving the cellular pool of KRASG12C towards the RAS(ON) state. These escape mechanisms, in which KRASG12C can be reactivated in the presence of a KRASG12C(OFF) inhibitor, highlight the potential for an inhibitor that directly targets and disables the KRASG12C(ON) form. Using structure-based drug design, we have discovered RM-032, a potent covalent inhibitor of KRASG12C(ON) that forms a tri-complex between KRASG12C(ON) and cyclophilin A (CypA), a highly abundant immunophilin. The assembled tri-complex prevents KRASG12C(ON) from signaling via steric blockade of RAS effector binding. In cells, kinetic analyses demonstrate near-immediate disruption of RAS effector binding and extinction of KRASG12C(ON) signaling. RM-032 is dual selective for KRASG12C(ON) and NRASG12C(ON). In vitro, RM-032 drives increased durability of inhibition of both RAS pathway signaling and cell proliferation in KRASG12C tumor cells compared with KRASG12C(OFF) inhibition. RM-032 displays attractive drug-like properties including cross-species oral bioavailability, and is predicted to achieve adequate exposures following oral dosing in humans. Oral administration of RM-032 produces deep and durable suppression of RAS pathway activity in KRASG12C tumor models and drives profound tumor regressions in vivo at well-tolerated doses. Across multiple tumor xenograft models, advanced KRASG12C(ON) inhibitors, including RM-032, appear to outperform KRASG12C(OFF) inhibitors. RM-032 permits a broad array of combination opportunities for treating KRASG12C mutant cancer types where single agent KRASG12C(ON) inhibition may be insufficient, for example with agents targeting nodes both upstream (e.g., SHP2 and SOS1) and downstream (e.g., MEK and ERK) of RAS, as well as parallel pathways (e.g., mTORC1). RM-032 is a next generation mutant-selective inhibitor of KRASG12C(ON) that may overcome liabilities of first-generation KRASG12C(OFF) inhibitors and provide additional benefit to patients by directly targeting the active form of this important oncogenic driver mutation. Citation Format: Robert J. Nichols, Jim Cregg, Christopher J. Schulze, Zhican Wang, Kevin Yang, Jingjing Jiang, Daniel M. Whalen, Rich Hansen, Lindsay S. Garrenton, Alun Bermingham, John E. Knox, Tiffany Choy, Denise Reyes, Mayra Rios, Kyle Seamon, Michael Longhi, Kang-Jye Chou, Shaoling Li, David P. Wildes, Mallika Singh, Elena S. Koltun, Adrian L. Gill, Jacqueline A. M. Smith. A next generation tri-complex KRASG12C(ON) inhibitor directly targets the active, GTP-bound state of mutant RAS and may overcome resistance to KRASG12C(OFF) inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1261.