Abstract ND03: Discovery of RMC-9805, an oral, covalent tri-complex KRASG12D(ON) inhibitor

Abstract RASG12D mutant cancers represent a significant unmet medical need with 55,000 new diagnoses annually in the US. The RASG12D mutation increases the abundance of the active, GTP-bound state of RAS (RASG12D(ON)) and occurs commonly in multiple tumor histotypes, including about 20%, 29% and 17% of RAS mutant colorectal, pancreatic, and non-small cell lung cancers, respectively. RMC-6236, an investigational RASMULTI(ON) inhibitor currently in clinical testing, selectively targets the active, GTP-bound state of both mutant and wild-type RAS variants, including RASG12D(ON) and has shown clinical anti-tumor activity against tumors harboring KRASG12D. Efforts to find a mutant-selective RASG12D(ON) inhibitor led to the discovery of RMC-9805.The investigational agent RMC-9805 is a first-in-class, orally bioavailable, mutant selective covalent inhibitor of RASG12D(ON) that forms a tri-complex between the abundant intracellular chaperone cyclophilin A (CypA) and the “ON” state of RASG12D, enabling selective covalent engagement of Asp-12 and disrupting downstream RAS signaling by steric occlusion of effector binding. In contrast to other examples in the literature of covalent inhibitors of KRASG12D that rely on highly reactive, low stability warheads to overcome the low intrinsic reactivity of aspartic acid, RMC-9805 employs a warhead with low intrinsic reactivity and high stability under biological conditions. Rapid, selective, covalent modification of RASG12D by RMC-9805 is enabled by our tri-complex technology. We used structure-guided design to position the warhead in the CypA-RAS interface in an optimal orientation that enhanced crosslinking of Asp-12 allowing us to use a warhead that showed no intrinsic reactivity to a model aspartic acid system and was stable to enable oral dosing. RMC-9805 drove selective and persistent covalent modification of KRASG12D in human cancer cell lines in vitro, leading to deep and durable suppression of RAS pathway activity, inhibition of cell proliferation, and apoptosis. RMC-9805 monotherapy induced tumor regressions at well-tolerated doses in a majority of preclinical PDAC and NSCLC models harboring KRASG12D. Though a more heterogeneous response was observed in KRASG12D CRC models, combinations of RMC-9805 with either RMC-6236 (RASMULTI(ON) inhibitor) or an anti-EGFR antibody improved the depth of response and delayed the onset of resistance in vivo. In addition, RMC-9805 promoted cancer-associated neoantigen recognition and synergized with immunotherapy in preclinical models. RMC-9805 is also CNS penetrant and drove regressions in intracranial xenograft models of human KRASG12D PDAC. RMC-9805 is a first-in-class orally bioavailable, mutant selective and covalent RASG12D inhibitor currently in Phase 1 clinical trial (NCT06040541). Citation Format: John E. Knox, G. Leslie Burnett, Caroline Weller, Lingyan Jiang, Dongyu Zhang, Nicole Vita, Abby Marquez, Kyle J. Seamon, Andrea Gould, Marie Menard, Elsa Quintana, Zhe Chen, Zhican Wang, Zhengping Wang, Elena S. Koltun, Malika Singh, Jingjing Jiang, David Wildes, Jacqueline A.M. Smith, Adrian L. Gill. Discovery of RMC-9805, an oral, covalent tri-complex KRASG12D(ON) inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND03.