title: Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models.
abstract: OBJECTIVE
  We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers.
  
  
  METHODS
  The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents.
  
  
  RESULTS
  GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents.
  
  
  CONCLUSIONS
  GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling.
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Nannini
authors.forename: Brian B
authors.initials: BB
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Degtyarev
authors.forename: Jason
authors.initials: J
authors.lastname: Oeh
authors.forename: Heidi
authors.initials: H
authors.lastname: Savage
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Guan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hong
authors.forename: Robert
authors.initials: R
authors.lastname: Kassees
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.forename: Tyler
authors.initials: T
authors.lastname: Risom
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.forename: Bianca M
authors.initials: BM
authors.lastname: Liederer
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Skelton
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Wallin
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Punnoose
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Kui
authors.initials: K
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C583616:ipatasertib; D051057:Proto-Oncogene Proteins c-akt