GDC-0068 is a potent, highly selective, orally available, ATP-competitive pan-AKT inhibitor, targeting Akt1, Akt2 and Akt3 with IC50 of 5 nM, 18 nM and 8 nM, respectively. It demonstrates high selectivity
over more than 200 screened kinases, with >100 fold selectivity for Akt over PKA [1-4].

Akt functions as a central role of the PI3K-Akt-mTOR pathway. It is one of the most frequently activated protein serine/threonine kinases in human malignancies. Inhibiting Akt activity has become an attractive approach for cancer treatment. GDC-0068 blocks the phosphorylation of multiple downstream targets of Akt in human cancer cell lines in a dose-dependent manner. It inhibits cell cycle progression and viability of cancer cell lines, most robustly in cells with activated PI3K-Akt-mTOR pathway driven by PIK3CA , PTEN loss and HER2 amplification. GDC-0068 treatment results in pronounced PD effects in tumor xenograft models including dose dependent suppression of p-PRAS40, P-S6 and P-eIF4G, as well as induction of FOXO nuclear localization. GDC-0086 has exhibited antitumor efficacy in multiple xenograft tumor models. In addition, consistent with the role of Akt in a survival pathway, GDC-0068 also demonstrates enhanced antitumor efficacy when combined with other therapeutic agents. GDC-0068 is currently in Phase 1a and Phase 1b clinical development in cancer patients [1-4].