Structure-Based Design of ASK1 Inhibitors as Potential Agents for Heart Failure

  • ACS Med Chem Lett. 2017 Feb 8;8(3):316-320. doi: 10.1021/acsmedchemlett.6b00481.
Marion Lanier  1 ,  Jason Pickens  1 ,  Simone V Bigi  1 ,  Erica L Bradshaw-Pierce  1 ,  Alison Chambers  1 ,  Zacharia S Cheruvallath  1 ,  Derek Cole  1 ,  Douglas R Dougan  1 ,  Jacques Ermolieff  1 ,  Tony Gibson  1 ,  Petro Halkowycz  1 ,  Aki Hirokawa  1 ,  Anthony Ivetac  1 ,  Joanne Miura  1 ,  Evan Nunez  1 ,  Mark Sabat  1 ,  John Tyhonas  1 ,  Haixia Wang  1 ,  Xiaolun Wang  1 ,  Steve Swann  1
Affiliations
  • 1. Departments of Medicinal Chemistry, Drug Metabolism Pharmacokinetics, Structural Biology, and Discovery Biology, Gastrointestinal Drug Discovery Unit, Takeda Pharmaceuticals , 10410 Science Center Drive, San Diego, California 92121, United States.
PMID: 28337323 DOI: 10.1021/acsmedchemlett.6b00481
Abstract

Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.

Keywords
Apoptosis signal-regulating kinase 1 (ASK1); cardiac injury; structure-based drug design (SBDD).
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