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

Marion Lanier; Jason Pickens; Simone V Bigi; Erica L Bradshaw-Pierce; Alison Chambers; Zacharia S Cheruvallath; Derek Cole; Douglas R Dougan; Jacques Ermolieff; Tony Gibson; Petro Halkowycz; Aki Hirokawa; Anthony Ivetac; Joanne Miura; Evan Nunez; Mark Sabat; John Tyhonas; Haixia Wang; Xiaolun Wang; Steve Swann

doi:10.1021/acsmedchemlett.6b00481

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. eCollection 2017 Mar 9.

Authors

Marion Lanier¹, Jason Pickens¹, Simone V Bigi¹, Erica L Bradshaw-Pierce¹, Alison Chambers¹, Zacharia S Cheruvallath¹, Derek Cole¹, Douglas R Dougan¹, Jacques Ermolieff¹, Tony Gibson¹, Petro Halkowycz¹, Aki Hirokawa¹, Anthony Ivetac¹, Joanne Miura¹, Evan Nunez¹, Mark Sabat¹, John Tyhonas¹, Haixia Wang¹, Xiaolun Wang¹, Steve Swann¹

Affiliation

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.

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).