title: Discovery of spirocyclic sulfonamides as potent Akt inhibitors with exquisite selectivity against PKA.
abstract: We describe the design and synthesis of novel bicyclic spiro sulfonamides as potent Akt inhibitors. Through structure-based rational design, we have successfully improved PKA selectivity of previously disclosed spirochromanes. Representative compounds showed favorable Akt potency while exhibiting up to 1000-fold selectivity against PKA.
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301, USA. rxu@arraybiopharma.com
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.forename: Anna
authors.initials: A
authors.lastname: Banka
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.forename: Ian S
authors.initials: IS
authors.lastname: Mitchell
authors.forename: Eli M
authors.initials: EM
authors.lastname: Wallace
authors.forename: Josef R
authors.initials: JR
authors.lastname: Bencsik
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Kallan
authors.forename: Keith L
authors.initials: KL
authors.lastname: Spencer
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Matthew
authors.initials: M
authors.lastname: Martinson
authors.forename: Tyler
authors.initials: T
authors.lastname: Risom
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Gross
authors.forename: Tony H
authors.initials: TH
authors.lastname: Morales
authors.forename: Wen-I
authors.initials: WI
authors.lastname: Wu
authors.forename: Guy P A
authors.initials: GP
authors.lastname: Vigers
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brandhuber
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D013141:Spiro Compounds; D013449:Sulfonamides; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases