title: Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1.
abstract: The discovery and potency optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ~10nM, as exemplified by compound 12az. Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.
authors.affiliation: OSI Pharmaceuticals LLC, 1 Bioscience Park Drive, Farmingdale, NY 11735, USA. keith.hornberger@boehringer-ingelheim.com
authors.forename: Keith R
authors.initials: KR
authors.lastname: Hornberger
authors.forename: Dan M
authors.initials: DM
authors.lastname: Berger
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Crew
authors.forename: Hanqing
authors.initials: H
authors.lastname: Dong
authors.forename: Andrew
authors.initials: A
authors.lastname: Kleinberg
authors.forename: An-Hu
authors.initials: AH
authors.lastname: Li
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Medeiros
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulvihill
authors.forename: Kam
authors.initials: K
authors.lastname: Siu
authors.forename: James
authors.initials: J
authors.lastname: Tarrant
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Felix
authors.initials: F
authors.lastname: Weng
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Wilde
authors.forename: Mark
authors.initials: M
authors.lastname: Albertella
authors.forename: Mark
authors.initials: M
authors.lastname: Bittner
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooke
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gray
authors.forename: Paul
authors.initials: P
authors.lastname: Maresca
authors.forename: Earl
authors.initials: E
authors.lastname: May
authors.forename: Peter
authors.initials: P
authors.lastname: Meyn
authors.forename: William
authors.initials: W
authors.lastname: Peick
authors.forename: Darlene
authors.initials: D
authors.lastname: Romashko
authors.forename: Michael
authors.initials: M
authors.lastname: Tanowitz
authors.forename: Brianna
authors.initials: B
authors.lastname: Tokar
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000588:Amines; D004791:Enzyme Inhibitors; D005663:Furans; D020930:MAP Kinase Kinase Kinases; D011725:Pyridines; D000099151:MAP Kinase Kinase Kinase 7
keywords: 7-Amino-furo[2,3-c]pyridine; Cancer; Inflammation; Inhibitors; TAK1