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Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

¹ Oncology Biology, ² Medicinal Chemistry, ³ Discovery Technology Group, ⁴ Enzymology and Mechanistic Pharmacology, ⁵ Drug Metabolism and Pharmacokinetics, and ⁶ Assay Development, GlaxoSmithKline, Collegeville, Pennsylvania

Requests for reprints: Rakesh Kumar, Oncology Biology, 1250 South Collegeville Road, UP1450, Collegeville, PA 19426. Phone: 610-917-4855; Fax: 610-917-4181; E-mail: rakesh.2.kumar{at}gsk.com.

Key Words: Akt • kinase inhibitor • pharmacodynamics

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 GSK3β, 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 GSK3β phosphorylation in a dose- and time-dependent manner. After a single dose of GSK690693, >3 µmol/L drug concentration in BT474 tumor xenografts correlated with a sustained decrease in GSK3β 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. [Cancer Res 2008;68(7):2366–74]