Abstract B137: Selective inhibition of the active state of KRASG12V with the non-covalent, tri-complex inhibitor RM-048
Authors: Lee Bianca J , Cregg Jim , Edwards Anne , Chen Jerry , Eriksson Andre , Tonogai Emily , Tomlinson Aidan , Seamon Kyle , Ayala Mariela Moreno , Shifrin Nataliya Tovbis , Montazer Nilufar , Sanders Kate , Huang Jun , Chou Kang-Jye , Madej Benjamin , Liu Yang , Wang Zhican , Wang Zhengping , Knox John , Koltun Elena , Jiang Jingjing , Gill Adrian , Smith Jacqueline A.M. 
Published: December 2023

Abstract
The KRASG12V mutation is the second most common oncogenic RAS mutation and is frequently observed in pancreatic, lung, and colorectal cancers. Developing a selective inhibitor of KRASG12V presents significant drug discovery challenges. The intrinsic GTP hydrolysis rate of KRASG12V is about 12-fold lower than that of KRASG12C, further biasing the cellular KRASG12V pool to the active, GTP-bound (“RAS(ON)”) state and emphasizing the importance of targeting the KRASG12V(ON) state for maximal suppression of this oncogenic driver. Additionally, achieving selectivity over wild-type RAS with small molecules is difficult because the valine residue introduced by KRASG12V is neither amenable to covalent inhibition nor to formation of polar, non-covalent interactions. We have previously applied our tri-complex inhibitor platform, which uses chemical re-remodeling of the cellular chaperone cyclophilin A (CypA) in order to bind to undruggable surfaces, to design mutant-selective inhibitors targeting KRASG12C, KRASG13C, KRASG12D, and KRASQ61H, in addition to the RASMULTI inhibitor RMC-6236. Here, we describe RM-048, a potent, selective, and oral tri-complex inhibitor of KRASG12V(ON). RM-048 binds to CypA with high affinity to form a binary complex. Binding to CypA creates a neomorphic interface that forms a selective, high-affinity, non-covalent interaction with KRASG12V(ON). The resulting tri-complex sterically blocks effector binding to KRASG12V(ON), thereby inhibiting downstream signaling. RM-048 potently suppressed ERK phosphorylation and proliferation in KRASG12V mutant cancer cells. In preclinical species, RM-048 showed good bioavailability, dose-proportional exposure, and low clearance, allowing for oral dosing. In human xenograft tumors harboring KRASG12V mutations, a single dose of RM-048 induced dose-dependent, deep, and durable suppression of RAS pathway signaling in vivo. Repeated daily oral administration of RM-048 was well tolerated and demonstrated profound anti-tumor activity, driving tumor regressions across a panel of KRASG12V xenograft models, including NSCLC, PDAC, and CRC models. RM-048 complements the mutant-selective tri-complex KRAS(ON) inhibitors RMC-6291 (KRASG12C) and RMC-9805 (KRASG12D) by potentially providing a mutant-selective inhibitor option for patients with tumors harboring one of the most frequent RAS mutations. Preclinical combination studies with RAS companion inhibitors, including the RASMULTI inhibitor RMC-6236, are ongoing.
Citation Format: Bianca J Lee, Jim Cregg, Anne Edwards, Jerry Chen, Andre Eriksson, Emily Tonogai, Aidan Tomlinson, Kyle Seamon, Mariela Moreno Ayala, Nataliya Tovbis Shifrin, Nilufar Montazer, Kate Sanders, Jun Huang, Kang-Jye Chou, Benjamin Madej, Yang Liu, Zhican Wang, Zhengping Wang, John Knox, Elena Koltun, Jingjing Jiang, Adrian Gill, Jacqueline A.M. Smith. Selective inhibition of the active state of KRASG12V with the non-covalent, tri-complex inhibitor RM-048 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B137.