GDC-0068 (RG7440),1001264-89-6,IC-0198068

GDC-0068 (RG7440, Ipatasertib) is a novel highly selective ATP-competitive pan-Akt inhibitor that inhibits all three isoforms of Akt1, Akt2, and Akt3 at an IC50 of 5,18,8 nM, respectively [1,5].

GDC-0068 decreased cell viability, induced apoptosis, and inhibited phosphorylation of proline rich Akt substrate 40 kDa and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared with PIK3CA-wildtype cell lines[6]. The combined treatment of GDC-0068 (RG7440) plus anti-microtubule chemotherapy, including vinorelbine, paclitaxel, eribulin, is contributed to anti-proliferative, pro-apoptotic, and anti-metastatic effect on human breast cancer cells[7]. GDC-0068 (RG7440) blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 (RG7440) resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines[2].

Preclinical Pharmacology demonstrates GDC-0068 (RG7440) exposure resulting in a dose-dependently pharmacodynamic effect and robust anti-tumor activity in a broad spectrum of human cancer cells in vitro and in vivo[5]. GDC-0068 (RG7440) therapy significantly inhibited the growth of WT tumors, however, for the PUMA / tumors, GDC-0068 (RG7440) therapy caused some suppression, but not so markedly compared with that of WT tumors. Immunohistochemistry staining shows that the expression of P-Akt reduced in both WT and PUMA / tumors after GDC-0068 (RG7440) therapy. PUMA-dependent antitumor effects of GDC-0068 (RG7440) in colon cancer[4]. As an ATP-competitive Akt inhibitor, GDC-0068 (RG7440) is a strong and safe target for Akt, which has been proved in a first-in-human phase I study[3].