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

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

  • J Med Chem. 2021 Apr 8;64(7):3940-3955. doi: 10.1021/acs.jmedchem.0c02085.
Malcolm P Huestis 1,  Darlene Dela Cruz 2,  Antonio G DiPasquale 3,  Matthew R Durk 4,  Charles Eigenbrot 5,  Paul Gibbons 1,  Alberto Gobbi 1,  Thomas L Hunsaker 2,  Hank La 4,  Dennis H Leung 3,  Wendy Liu 1,  Shiva Malek 6,  Mark Merchant 2,  John G Moffat 7,  Christine S Muli 3,  Christine J Orr 2,  Brendan T Parr 1,  Frances Shanahan 6,  Christopher J Sneeringer 7,  Weiru Wang 5,  Ivana Yen 6,  Jianping Yin 5,  Michael Siu 1,  Joachim Rudolph 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2 Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 3 Small Molecule Pharmaceutical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 4 Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 5 Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 6 Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 7 Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
PMID: 33780623 DOI: 10.1021/acs.jmedchem.0c02085
Abstract

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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