GDC-0068 (RG7440) (Synonyms: Ipatasertib, RG-7440)

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].

References:
[1]. Lin K, Lin J, et,al. An ATP-site on-off switch that restricts phosphatase accessibility of Akt. Sci Signal. 2012 May 8;5(223):ra37. doi: 10.1126/scisignal.2002618. PMID: 22569334.
[2]. Lin J, Sampath D, et,al.Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 2013 Apr 1;19(7):1760-72. doi: 10.1158/1078-0432.CCR-12-3072. Epub 2013 Jan 3. PMID: 23287563.
[3]. Saura C, Roda D, et,al. A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors. Cancer Discov. 2017 Jan;7(1):102-113. doi: 10.1158/2159-8290.CD-16-0512. Epub 2016 Nov 21. Erratum in: Cancer Discov. 2018 Nov;8(11):1490. PMID: 27872130; PMCID: PMC5463454.
[4]. Sun L, Huang Y, et,al. Ipatasertib, a novel Akt inhibitor, induces transcription factor FoxO3a and NF-κB directly regulates PUMA-dependent apoptosis. Cell Death Dis. 2018 Sep 5;9(9):911. doi: 10.1038/s41419-018-0943-9. PMID: 30185800; PMCID: PMC6125489.
[5]. Blake JF, Xu R, et,al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem. 2012 Sep 27;55(18):8110-27. doi: 10.1021/jm301024w. Epub 2012 Sep 18. PMID: 22934575.
[6]. Ippen FM, Grosch JK, et,al. Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases. Neuro Oncol. 2019 Nov 4;21(11):1401-1411. doi: 10.1093/neuonc/noz105. PMID: 31173106; PMCID: PMC6827829.
[7]. Yan Y, Serra V, et,al.Evaluation and clinical analyses of downstream targets of the Akt inhibitor GDC-0068. Clin Cancer Res. 2013 Dec 15;19(24):6976-86. doi: 10.1158/1078-0432.CCR-13-0978. Epub 2013 Oct 18. PMID: 24141624.