title: 2,3,5-Trisubstituted pyridines as selective AKT inhibitors-Part I: Substitution at 2-position of the core pyridine for ROCK1 selectivity.
abstract: 2,3,5-Trisubstituted pyridines have been designed as potent AKT inhibitors that are selective against ROCK1 based on the comparison between AKT and ROCK1 structures. Substitution at the 2-position of the core pyridine is the key element to provide selectivity against ROCK1. An X-ray co-crystal structure of 9p in PKA supports the proposed rationale of ROCK1 selectivity.
authors.affiliation: Oncology Medicinal Chemistry, GlaxoSmithKline, 1250 S. Collegeville, Rd., Collegeville, PA 19426, United States. hong.2.lin@gsk.com
authors.forename: Hong
authors.initials: H
authors.lastname: Lin
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Yamashita
authors.forename: Jin
authors.initials: J
authors.lastname: Zeng
authors.forename: Ren
authors.initials: R
authors.lastname: Xie
authors.forename: Wenyong
authors.initials: W
authors.lastname: Wang
authors.forename: Sirishkumar
authors.initials: S
authors.lastname: Nidarmarthy
authors.forename: Juan I
authors.initials: JI
authors.lastname: Luengo
authors.forename: Nelson
authors.initials: N
authors.lastname: Rhodes
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Knick
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Choudhry
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lai
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Minthorn
authors.forename: Susan L
authors.initials: SL
authors.lastname: Strum
authors.forename: Edgar R
authors.initials: ER
authors.lastname: Wood
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Elkins
authors.forename: Nestor O
authors.initials: NO
authors.lastname: Concha
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Heerding
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases