Young K Chen, Toufike Kanouni, Lee D Arnold, Jason M Cox, Elisabeth Gardiner, Kathryn Grandinetti, Ping Jiang, Stephen W Kaldor, Catherine Lee, Chun Li, Eric S Martin, Nichol Miller, Eric A Murphy, Noel Timple, John S Tyhonas, Angie Vassar, Tim S Wang, Richard Williams, Ding Yuan, Robert S Kania
RAF, a core signaling component of the MAPK kinase cascade, is often mutated in various cancers, including melanoma, lung, and colorectal cancers. The approved inhibitors were focused on targeting the BRAFV600E mutation that results in constitutive activation of kinase signaling through the monomeric protein (Class I). However, these inhibitors also paradoxically activate kinase signaling of RAF dimers, resulting in increased MAPK signaling in normal tissues. Recently, significant attention has turned to targeting RAF alterations that activate dimeric signaling (class II and III BRAF and NRAS)...
January 17, 2024: Journal of Medicinal Chemistry