title: Discovery of 2-pyrimidyl-5-amidothiophenes as potent inhibitors for AKT: synthesis and SAR studies.
abstract: A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC(50) values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed.
authors.affiliation: Small Molecule Drug Discovery, Biopharma Research, Chiron Corporation, Emeryville, CA, USA. xiaodong_lin@chiron.com
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Lin
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Murray
authors.forename: Alice C
authors.initials: AC
authors.lastname: Rico
authors.forename: Michael X
authors.initials: MX
authors.lastname: Wang
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Chu
authors.forename: Yasheen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Merci
authors.initials: M
authors.lastname: Del Rosario
authors.forename: Susan
authors.initials: S
authors.lastname: Kaufman
authors.forename: Sylvia
authors.initials: S
authors.lastname: Ma
authors.forename: Eric
authors.initials: E
authors.lastname: Fang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Crawford
authors.forename: A B
authors.initials: AB
authors.lastname: Jefferson
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D013876:Thiophenes; D051057:Proto-Oncogene Proteins c-akt