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Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5‑Fluoro-4-(3H)‑quinazolinone Aryl Urea pan-RAF Kinase Inhibitor

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posted on 29.03.2021, 23:04 by Malcolm P. Huestis, Darlene Dela Cruz, Antonio G. DiPasquale, Matthew R. Durk, Charles Eigenbrot, Paul Gibbons, Alberto Gobbi, Thomas L. Hunsaker, Hank La, Dennis H. Leung, Wendy Liu, Shiva Malek, Mark Merchant, John G. Moffat, Christine S. Muli, Christine J. Orr, Brendan T. Parr, Frances Shanahan, Christopher J. Sneeringer, Weiru Wang, Ivana Yen, Jianping Yin, Michael Siu, Joachim Rudolph
Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing reliance on common polar hinge contacts, this hinge binder allows for a greater contribution of RAF-specific residue interactions, resulting in exquisite kinase selectivity. Strategic substitution of fluorine at the C5 position efficiently masked the adjacent polar NH functionality and increased solubility by impeding a solid-state conformation associated with stronger crystal packing of the molecule. The resulting improvements in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK inhibitor cobimetinib demonstrated synergistic pathway inhibition and significant tumor growth inhibition in a KRAS mutant xenograft mouse model.

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