Abstract 3296: IK-595, a best-in-class MEK-RAF molecular glue, drives broad and potent anti-tumor activity across RAS-MAPK pathway-altered cancers as a monotherapy and in combination
Authors: Haines Eric , Catterall Rachel , De Jesus Victor , Hidalgo Daniel , Cavanaugh Jill , Sanchez-Martin Marta , Manna Joseph D. , Burke Michael , Li Bin , Wessel Sarah R. , Yang Ao , Santillana Sergio , Ecsedy Jeffrey , Zhang X. Michelle , Ruppel Sabine K. 
Published: March 2024

Abstract
Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. Although MEK is a clinically validated cancer target and several MEK inhibitors have been approved by the FDA, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas. We developed the molecular glue, IK-595, a potent inhibitor of the MEK-RAF complex, to overcome the limitations of available MEK inhibitors. IK-595 traps MEK in an inactive complex with all RAF isoforms, as well as mutant forms of BRAF (Class I, II, and III), and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that limits the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors. We demonstrate that IK-595 leads to potent and prolonged inhibition of MEK and ERK1/2 phosphorylation in RAS-mutant cancer models. Importantly, IK-595 has a much slower off-rate binding to MEK and retains CRAF longer in an inactive complex with MEK than other MEK/RAF inhibitors, allowing for prolonged target engagement and durable pathway inhibition in RAS/RAF mutant cancer cells. IK-595 exhibits potent single agent activity across a wide range of cancer model indications harboring various RAS/MAPK pathway alterations, including KRAS, NRAS, BRAF and NF1 mutations, and BRAF and CRAF fusions. The benefits of combining IK-595 with inhibitors targeting key resistance mechanisms both within the RAS/MAPK pathway and across parallel survival pathways has also been observed in multiple models. Additionally, IK-595 improved the response of KRAS-driven tumor models to standard of care chemotherapeutic agents, expanding the potential clinical opportunity for IK-595. Key to the design of IK-595 is its PK profile that enables transient high plasma drug exposure and flexible dosing schedules. Intermittent dosing of IK-595 every other day (QOD) or every three days (Q3D) in KRAS-mutant mouse tumor models shows similar efficacy and improved tolerability compared to daily dosing (QD), affording a larger therapeutic window. Preclinical pharmacology studies provide clear guidance to the clinical development plan of IK-595, where flexible dosing schedules, multiple expansion cohorts in RAS/RAF altered patient populations, and combination therapies with mediators of resistance will be explored. IK-595 is a novel MEK-RAF molecular glue that prolongs pathway inhibition, minimizing the potential for resistance, while providing an optimal therapeutic window for patients with RAS/RAF-driven cancer.
Citation Format: Eric Haines, Rachel Catterall, Victor De Jesus, Daniel Hidalgo, Jill Cavanaugh, Marta Sanchez-Martin, Joseph D. Manna, Michael Burke, Bin Li, Sarah R. Wessel, Ao Yang, Sergio Santillana, Jeffrey Ecsedy, X. Michelle Zhang, Sabine K. Ruppel. IK-595, a best-in-class MEK-RAF molecular glue, drives broad and potent anti-tumor activity across RAS-MAPK pathway-altered cancers as a monotherapy and in combination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3296.