Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a Pyridopyridazinone pan-RAF Kinase Inhibitor

  • ACS Med Chem Lett. 2021 Apr 21;12(5):791-797. doi: 10.1021/acsmedchemlett.1c00063.
Malcolm P Huestis  1 ,  Matthew R Durk  2 ,  Charles Eigenbrot  3 ,  Paul Gibbons  1 ,  Thomas L Hunsaker  4 ,  Hank La  2 ,  Dennis H Leung  5 ,  Wendy Liu  1 ,  Shiva Malek  6 ,  Mark Merchant  4 ,  John G Moffat  7 ,  Christine S Muli  5 ,  Christine J Orr  4 ,  Brendan T Parr  1 ,  Frances Shanahan  6 ,  Christopher J Sneeringer  7 ,  Weiru Wang  3 ,  Ivana Yen  6 ,  Jianping Yin  3 ,  Joachim Rudolph  1 ,  Michael Siu  1
Affiliations
  • 1. Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 2. Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 3. Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 4. Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 5. Small Molecule Pharmaceutical Sciences, 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: 34055227 DOI: 10.1021/acsmedchemlett.1c00063
Abstract

Structure-based optimization of a set of aryl urea Raf inhibitors has led to the identification of Type II pan-RAF inhibitor GNE-9815 (7), which features a unique pyrido[2,3-d]pyridazin-8(7H)-one hinge-binding motif. With minimal polar hinge contacts, the pyridopyridazinone hinge binder moiety affords exquisite kinase selectivity in a lipophilic efficient manner. The improved physicochemical properties of GNE-9815 provided a path for oral dosing without enabling formulations. In vivo evaluation of GNE-9815 in combination with the MEK Inhibitor cobimetinib demonstrated synergistic MAPK pathway modulation in an HCT116 xenograft mouse model. To the best of our knowledge, GNE-9815 is among the most highly kinase-selective Raf inhibitors reported to date.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-142160
    GNE-9815
    98.94%, RAF Inhibitor
    target: Raf
    Research Areas: Cancer