title: Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity.
abstract: Akt kinases 1, 2, and 3 are important regulators of cell survival and have been shown to be constitutively active in a variety of human tumors. GSK690693 is a novel ATP-competitive, low-nanomolar pan-Akt kinase inhibitor. It is selective for the Akt isoforms versus the majority of kinases in other families; however, it does inhibit additional members of the AGC kinase family. It causes dose-dependent reductions in the phosphorylation state of multiple proteins downstream of Akt, including GSK3 beta, PRAS40, and Forkhead. GSK690693 inhibited proliferation and induced apoptosis in a subset of tumor cells with potency consistent with intracellular inhibition of Akt kinase activity. In immune-compromised mice implanted with human BT474 breast carcinoma xenografts, a single i.p. administration of GSK690693 inhibited GSK3 beta phosphorylation in a dose- and time-dependent manner. After a single dose of GSK690693, >3 micromol/L drug concentration in BT474 tumor xenografts correlated with a sustained decrease in GSK3 beta phosphorylation. Consistent with the role of Akt in insulin signaling, treatment with GSK690693 resulted in acute and transient increases in blood glucose level. Daily administration of GSK690693 produced significant antitumor activity in mice bearing established human SKOV-3 ovarian, LNCaP prostate, and BT474 and HCC-1954 breast carcinoma xenografts. Immunohistochemical analysis of tumor xenografts after repeat dosing with GSK690693 showed reductions in phosphorylated Akt substrates in vivo. These results support further evaluation of GSK690693 as an anticancer agent.
authors.affiliation: Oncology Biology, GlaxoSmithKline, Collegeville, PA 19426, USA.
authors.forename: Nelson
authors.initials: N
authors.lastname: Rhodes
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Heerding
authors.forename: Derek R
authors.initials: DR
authors.lastname: Duckett
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Eberwein
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Knick
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Lansing
authors.forename: Randy T
authors.initials: RT
authors.lastname: McConnell
authors.forename: Tona M
authors.initials: TM
authors.lastname: Gilmer
authors.forename: Shu-Yun
authors.initials: SY
authors.lastname: Zhang
authors.forename: Kimberly
authors.initials: K
authors.lastname: Robell
authors.forename: Jason A
authors.initials: JA
authors.lastname: Kahana
authors.forename: Robert S
authors.initials: RS
authors.lastname: Geske
authors.forename: Elena V
authors.initials: EV
authors.lastname: Kleymenova
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Choudhry
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Lai
authors.forename: Jack D
authors.initials: JD
authors.lastname: Leber
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: Pearl S
authors.initials: PS
authors.lastname: Huang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010069:Oxadiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C528328:GSK690693; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt