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
  • 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.