title: Structure-based drug design of novel ASK1 inhibitors using an integrated lead optimization strategy.
abstract: Structure-based drug design is an iterative process that is an established means to accelerate lead optimization, and is most powerful when integrated with information from different sources. Herein is described the use of such methods in conjunction with deconstruction and re-optimization of a diverse series of ASK1 chemotypes along with high-throughput screening that lead to the identification of a novel series of efficient ASK1 inhibitors displaying robust MAP3K pathway inhibition.
authors.affiliation: Medicinal Chemistry Gastrointestinal Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States. Electronic address: tony.gibson@takeda.com.
authors.forename: Tony S
authors.initials: TS
authors.lastname: Gibson
authors.affiliation: Medicinal Chemistry CNS Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Discovery Biology Gastrointestinal Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fanjul
authors.affiliation: Discovery Biology Gastrointestinal Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Petro
authors.initials: P
authors.lastname: Halkowycz
authors.affiliation: Structural Biology and Biophysics, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Dougan
authors.affiliation: Medicinal Chemistry Gastrointestinal Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Derek
authors.initials: D
authors.lastname: Cole
authors.affiliation: Medicinal Chemistry Gastrointestinal Drug Discovery Unit, Takeda California Inc., 10410 Science Center Drive, San Diego, CA 92121, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Swann
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D048848:MAP Kinase Kinase Kinase 5
keywords: Apoptosis signal-regulating kinase 1 (ASK1); Structure-based drug design (SBDD)