title: Discovery of pyrrolopyrimidine inhibitors of Akt.
abstract: The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts.
authors.affiliation: Array BioPharma Inc, 3200 Walnut Street, Boulder, CO 80301, USA. jblake@arraybiopharma.com
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Kallan
authors.forename: Dengming
authors.initials: D
authors.lastname: Xiao
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.forename: Josef R
authors.initials: JR
authors.lastname: Bencsik
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
authors.forename: Keith L
authors.initials: KL
authors.lastname: Spencer
authors.forename: Ian S
authors.initials: IS
authors.lastname: Mitchell
authors.forename: Richard D
authors.initials: RD
authors.lastname: Woessner
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Tyler
authors.initials: T
authors.lastname: Risom
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Gross
authors.forename: Matthew
authors.initials: M
authors.lastname: Martinson
authors.forename: Tony H
authors.initials: TH
authors.lastname: Morales
authors.forename: Guy P A
authors.initials: GP
authors.lastname: Vigers
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brandhuber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine; D051057:Proto-Oncogene Proteins c-akt