Abstract P252: IMM-1-104: a novel, oral, selective dual-MEK inhibitor that displays broad antitumor activity and high tolerability across RAS and RAF mutant tumors in vivo
Authors: King Peter J. , Fowler Kevin D. , Kolitz Sarah E. , Barrett Scott , Zeskind Benjamin J. , Hall Brett M. 
Published: December 2021

Abstract
Background: Inappropriate activation of the MAPK pathway, often stemming from mutations in RAS or RAF, represents one of the most common oncogenic events in human cancer. Therefore, MEK1 and MEK2 (MEK), which lie downstream of RAS and RAF but upstream of ERK, have represented an attractive drug target for over two decades. Unfortunately, first generation MEK inhibitors have been limited by pathway reactivation events and serious on-target drug toxicities that restrain clinical utility, especially in patients with RAS mutant tumors. We sought to develop a new approach to MEK inhibition that would be more effective in RAS mutant tumors and with improved tolerability. IMM-1-104 is a novel dual-MEK inhibitor that is designed to disrupt phosphorylation of MEK and subsequently prevent activation of ERK1 and ERK2 (ERK). IMM-1-104’s dual-MEK mechanism resists RAF activation of MEK, and its short drug half-life allows for chronic dosing while maintaining a near-zero drug trough for improved tolerability. Materials & Methods: IMM-1-104 was profiled across a series of preclinical experiments to assess its physicochemical and drug-like properties. Cell-free and cell-based in vitro as well as in vivo characteristics were evaluated, including four independent in vivo pharmacology rodent studies in lung, colon and skin tumor models. Results: IMM-1-104 is a highly selective, orally bioavailable, non-ATP competitive, allosteric dual-MEK inhibitor. At drug exposures up to 1 micromolar (uM) in cell-free and in situ kinome screens, thermodynamic interactions and altered activity levels were observed for MEK1 and MEK2. At higher drug exposures up to 10 uM, IMM-1-104 also thermodynamically interacted with RAF1 (CRAF) and prompted reduction of KSR1 and KSR2 activation markers. IMM-1-104 displayed dual-MEK activity (i.e., RAS mutant tumor cell reductions in both ERK and MEK phosphorylation) across multiple human tumor cell-based models including A549 (KRAS-G12S) lung, A375 (BRAF-V600E) and SK-MEL-2 (NRAS-Q61R) melanoma. Pharmacokinetic studies in rodent models revealed a drug plasma half-life for IMM-1-104 of approximately 1.3 hours. In vivo tumor pharmacology studies in A549 and A375 achieved tumor stasis (i.e., 85% to 95% Tumor Growth Inhibition) with regressions observed in Colon-26 and SK-MEL-2. Conclusions: The dual-MEK mechanism and short half-life of IMM-1-104 has proven to be broadly active and well-tolerated in multiple RAS and RAF mutant preclinical tumor models in rodents. IMM-1-104 drives deep, cyclic inhibition of the MAPK pathway (improving tolerability) while resisting pathway bypass mechanisms (improving activity). Our collective data suggest that RAS and RAF mutant tumor cells are not able to tolerate periods of deep but cyclic MAPK pathway inhibition. Overall, these results are consistent with on and off signaling events that can significantly impact cell fate decisions (i.e. signaling dynamics).
Citation Format: Peter J. King, Kevin D. Fowler, Sarah E. Kolitz, Scott Barrett, Benjamin J. Zeskind, Brett M. Hall. IMM-1-104: a novel, oral, selective dual-MEK inhibitor that displays broad antitumor activity and high tolerability across RAS and RAF mutant tumors in vivo [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P252.