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Ref Type abstract
Authors Eric Haines; Michael Burke; Rachel Catterall; Victor De Jesus; Bin Li; Joseph D. Manna; George Punkosdy; Oksana Zavidij; Sarah R. Wessel; Grace Werosta; Jill Cavanaugh; Sheila Newhouse; Aravind Basavapathruni; Lan Xu; Sergio Santillana; X. Michelle Zhang; Sabine K. Ruppel
Title Abstract PR10: IK-595, a MEK-RAF complex inhibitor, obviates CRAF mediated resistance resulting in superior RAS/MAPK pathway inhibition and anti-tumor activity in RAS/RAF altered cancers
Abstract Text 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 is limited to BRAFV600 mutant cancers and NF1 mutant neurofibromas. The limitations of these approved MEK inhibitors are inherently related to a narrow therapeutic window and their inability to completely inhibit MAPK signaling. Specifically, RAS mutant cancer cells have a stronger dependency on CRAF for MAPK signal transduction. The MEK inhibition and the subsequent reduction of phosphorylated ERK (pERK) by the approved MEK inhibitors triggers the relief of the ERK-dependent negative feedback control on CRAF, leading to CRAF mediated MEK reactivation and pERK rebound. In addition, CRAF has kinase independent functions that contribute to its anti-tumor apoptotic activities. We developed IK-595, a potent inhibitor of the MEK-RAF complex, to overcome the limitations of available MEK inhibitors. IK-595 stabilizes the MEK-BRAF and MEK-CRAF protein complexes both biochemically and in cells. By trapping MEK in an inactive complex with RAF, it blocks RAF-dependent MEK phosphorylation, limiting CRAF mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS mutant tumors. Importantly, IK-595 demonstrates persistent and further inhibition of ERK phosphorylation than trametinib and VS-6766. This translates to potent inhibition of cell proliferation across a variety of MAPK pathway altered cancer cell lines, including cells with KRAS and NRAS mutations and RAF alterations. Moreover, IK-595 synergizes with KRASG12C, pan-RAF, and mTOR inhibitors in vitro, leading to enhanced anti-proliferation in cancer cells. In addition, IK-595 inhibits MEK and ERK phosphorylation and ERK target gene DUSP6 expression in vivo, driving robust anti-tumor efficacy in multiple KRAS and NRAS mutant, and CRAF amplified, mouse tumor models. Lastly, the pharmacokinetic properties of IK-595 provide a broader therapeutic window compared to available MEK inhibitors. Together, IK-595 is a novel MEK-RAF complex inhibitor that prolongs pathway inhibition, minimizing the potential for resistance, while providing an optimal therapeutic window for patients.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
IK-595 IK-595 1 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
IK-595 IK595|IK 595 IK-595 inhibits the MEK-RAF complex, which potentially results in reduced tumor cell proliferation and decreased tumor growth (Mol Cancer Res (2023) 21 (5_Supplement): PR10).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS mutant Advanced Solid Tumor predicted - sensitive IK-595 Preclinical Actionable In a preclinical study, IK-595 inhibited Mek and Erk phosphorylation and decreased tumor growth in an NRAS-mutant mouse tumor model (Mol Cancer Res (2023) 21 (5_Supplement): PR10). detail...