title: Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors.
abstract: A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/β-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/β-catenin transcriptional complex.
authors.affiliation: Astex Pharmaceuticals, Inc., 2401 South Foothill Drive, Salt Lake City, UT 84109, USA. kanho99@yahoo.com
authors.forename: Koc-Kan
authors.initials: KK
authors.lastname: Ho
authors.forename: K Mark
authors.initials: KM
authors.lastname: Parnell
authors.forename: Yi
authors.initials: Y
authors.lastname: Yuan
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kultgen
authors.forename: Steven
authors.initials: S
authors.lastname: Hamblin
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Hendrickson
authors.forename: Bai
authors.initials: B
authors.lastname: Luo
authors.forename: Jason M
authors.initials: JM
authors.lastname: Foulks
authors.forename: Michael V
authors.initials: MV
authors.lastname: McCullar
authors.forename: Steven B
authors.initials: SB
authors.lastname: Kanner
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D017346:Protein Serine-Threonine Kinases; C545105:TNIK protein, mouse