Abstract 1598: RM-046, a first-in-class, mutant-selective, and oral KRASQ61H(ON) inhibitor that drives tumor regression in preclinical models and validates KRASQ61H as a therapeutic target
Authors: Yang Yu C. , Thompson Severin , Montgomery David , Quiñones Antonio J. , Wei Xing , Madej Benjamin , Tomlinson Aidan , Shifrin Nataliya T. , McNamara Alexander , Ahler Ethan , McDowell Laura L. , Flagella Michael , Setser John , Chang Stephanie , Wang Zhican , Wang Zhengping , Huang Jun , Ballmer Steve , li Shaong , Buckl Andreas , Koltun Elena , Gill Adrian , Jiang Jingjing , Singh Mallika , Smith Jacqueline A. 
Published: April 2023

KRASQ61H mutant cancers represent a significant unmet medical need and include common solid tumor histotypes such as non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC). Currently, there are no targeted inhibitors of KRASQ61H in clinical development. Mutant RAS proteins exist predominantly in the GTP-bound active RAS(ON) state, leading to excessive downstream signaling via interaction with effectors such as RAF kinases. The properties of the intrinsic GTPase cycle of KRASQ61H should lead to accumulation of the active ON state. RM-046 is a potent, selective, and oral tri-complex inhibitor of KRASQ61H(ON). RM-046 binds to the abundant intracellular chaperone protein cyclophilin A (CypA) with high affinity to form a binary complex that then non-covalently and selectively engages the active ON state of KRASQ61H. The resulting tri-complex sterically blocks KRASQ61H binding to its effectors, thereby inhibiting its downstream signaling. RM-046 potently suppressed ERK phosphorylation and proliferation in KRASQ61H mutant cancer cells with sub-nanomolar EC50 and IC50 values while displaying selectivity over cancer cells with wildtype KRAS. RM-046 showed no evidence of off-target interactions based on in vitro GTPase, kinome, and safety panels. As a single agent, RM-046 induced dose-dependent, deep, and durable suppression of RAS pathway signaling in preclinical xenograft models in vivo. Daily oral administration of RM-046 demonstrated dose-dependent anti-tumor activity and drove deep tumor regressions across several preclinical xenograft models of human KRASQ61H tumors, including NSCLC and PDAC. All treatment regimens tested with RM-046 were tolerated in vivo. As far as we are aware, RM-046 is the first oral and mutant-selective inhibitor of KRASQ61H(ON). It also represents an example of a non-covalent, mutant-selective tri-complex inhibitor of a KRAS oncogenic driver mutation.

Citation Format: Yu C. Yang, Severin Thompson, David Montgomery, Antonio J. Quiñones, Xing Wei, Benjamin Madej, Aidan Tomlinson, Nataliya T. Shifrin, Alexander McNamara, Ethan Ahler, Laura L. McDowell, Michael Flagella, John Setser, Stephanie Chang, Zhican Wang, Zhengping Wang, Jun Huang, Steve Ballmer, Shaong li, Andreas Buckl, Elena Koltun, Adrian Gill, Jingjing Jiang, Mallika Singh, Jacqueline A. Smith. RM-046, a first-in-class, mutant-selective, and oral KRASQ61H(ON) inhibitor that drives tumor regression in preclinical models and validates KRASQ61H as a therapeutic target [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 1598.