Fragment-based identification and optimization of a class of potent pyrrolo[2,1-f][1,2,4]triazine MAP4K4 inhibitors

  • Bioorg Med Chem Lett. 2014 Sep 15;24(18):4546-4552. doi: 10.1016/j.bmcl.2014.07.071.
Lan Wang  1 ,  Mark Stanley  1 ,  Jason W Boggs  2 ,  Terry D Crawford  1 ,  Brandon J Bravo  3 ,  Anthony M Giannetti  3 ,  Seth F Harris  4 ,  Steven R Magnuson  1 ,  Jim Nonomiya  3 ,  Stephen Schmidt  3 ,  Ping Wu  4 ,  Weilan Ye  5 ,  Stephen E Gould  5 ,  Lesley J Murray  2 ,  Chudi O Ndubaku  6 ,  Huifen Chen  7
Affiliations
  • 1. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 2. Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 3. Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 4. Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 5. Department of Molecular Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
  • 6. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
  • 7. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: [email protected].
PMID: 25139565 DOI: 10.1016/j.bmcl.2014.07.071
Abstract

MAP4K4 has been shown to regulate key cellular processes that are tied to disease pathogenesis. In an effort to generate small molecule MAP4K4 inhibitors, a fragment-based screen was carried out and a pyrrolotriazine fragment with excellent ligand efficiency was identified. Further modification of this fragment guided by X-ray crystal structures and molecular modeling led to the discovery of a series of promising compounds with good structural diversity and physicochemical properties. These compounds exhibited single digit nanomolar potency and compounds 35 and 44 achieved good in vivo exposure.

Keywords
Fragment-based lead discovery; Kinase inhibitors; MAP4K4; P-loop conformation; Pyrrolotriazine.
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