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¹ Cancer Research, ² Structural Biology, and ³ Metabolic Disease Research, Abbott Laboratories, Abbott Park, Illinois and ⁴ Idun Pharmaceuticals, San Diego, California

Requests for reprints: Vincent L. Giranda, Cancer Research, Abbott Laboratories, 100 Abbott Park Road, IL 60064-6117. Phone: 847-937-0268; Fax: 847-938-2365. E-mail: vincent.giranda{at}abbott.com

The Akt kinases are central nodes in signal transduction pathways that are important for cellular transformation and tumor progression. We report the development of a series of potent and selective indazole-pyridine based Akt inhibitors. These compounds, exemplified by A-443654 (K_i = 160 pmol/L versus Akt1), inhibit Akt-dependent signal transduction in cells and in vivo in a dose-responsive manner. In vivo, the Akt inhibitors slow the progression of tumors when used as monotherapy or in combination with paclitaxel or rapamycin. Tumor growth inhibition was observed during the dosing interval, and the tumors regrew when compound administration was ceased. The therapeutic window for these compounds is narrow. Efficacy is achieved at doses 2-fold lower than the maximally tolerated doses. Consistent with data from knockout animals, the Akt inhibitors induce an increase in insulin secretion. They also induce a reactive increase in Akt phosphorylation. Other toxicities observed, including malaise and weight loss, are consistent with abnormalities in glucose metabolism. These data show that direct Akt inhibition may be useful in cancer therapy, but significant metabolic toxicities are likely dose limiting.

Grant support: R. de Jong is currently at the Syrrx, Inc., 10410 Science Center Drive, San Diego, CA 92121.

Received 1/ 6/05; revised 3/16/05; accepted 4/11/05.