title: Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors.
abstract: The discovery and optimization of a series of 6,7-dihydro-5H-cyclopenta[d]pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, 28 (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase-Akt-mammalian target of rapamycin pathway is activated. 28 is currently being evaluated in human clinical trials for the treatment of cancer.
authors.affiliation: Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301, USA. jblake@arraybiopharma.com
authors.forename: James F
authors.initials: JF
authors.lastname: Blake
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.forename: Josef R
authors.initials: JR
authors.lastname: Bencsik
authors.forename: Dengming
authors.initials: D
authors.lastname: Xiao
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Kallan
authors.forename: Stephen
authors.initials: S
authors.lastname: Schlachter
authors.forename: Ian S
authors.initials: IS
authors.lastname: Mitchell
authors.forename: Keith L
authors.initials: KL
authors.lastname: Spencer
authors.forename: Anna L
authors.initials: AL
authors.lastname: Banka
authors.forename: Eli M
authors.initials: EM
authors.lastname: Wallace
authors.forename: Susan L
authors.initials: SL
authors.lastname: Gloor
authors.forename: Matthew
authors.initials: M
authors.lastname: Martinson
authors.forename: Richard D
authors.initials: RD
authors.lastname: Woessner
authors.forename: Guy P A
authors.initials: GP
authors.lastname: Vigers
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brandhuber
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Brian S
authors.initials: BS
authors.lastname: Safina
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Birong
authors.initials: B
authors.lastname: Zhang
authors.forename: Christine
authors.initials: C
authors.lastname: Chabot
authors.forename: Steven
authors.initials: S
authors.lastname: Do
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Brian B
authors.initials: BB
authors.lastname: Lee
authors.forename: Kui
authors.initials: K
authors.lastname: Lin
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C583616:ipatasertib; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt