Abstract

Akt activity is frequently elevated in cancer via multiple mechanisms, including loss of function of the PTEN tumor suppressor gene or mutations/amplifications of the PIK3CA or Akt genes1. Akt pathway activation is associated with poor prognosis and may lead to chemoresistance2. GDC-0068 inhibits all 3 isoforms of Akt (IC50 5-30 nM), with high selectivity over other kinases, including > 100-fold selectivity over the closely related protein kinase A3. In vitro, GDC-0068 shows synergistic anti-tumor activity when combined with cytotoxic agents, including docetaxel, 5-fluorouracil, and platinum chemotherapy4. In an ongoing Phase Ia study, GDC-0068 has been well tolerated with maximum tolerated dose (MTD) of 600 mg daily (21 days on/7 days off); pharmacodynamic down-regulation of Akt signaling in tumors has been observed at doses ≥ 100 mg.