Akt functions as a key component in multiple signaling pathways including those related to cell proliferation, metabolism, and survival as well as angiogenesis. AZD 5363 is a pyrrolopyrimidine-derived compound that inhibits Akt by competitively binding to the kinase domain, preventing substrate phosphorylation by Akt. It inhibits Akt1, 2, and 3 with IC50 values of 3, 7, and 7 nM, respectively and also inhibits P70S6K and PKA with similar potency (IC50s = 6 and 7 nM, respectively). Furthermore, AZD 5363 shows >75% inhibition at 1 μM against ROCK2, MKK1, MSK1, MSK2, PKCγ, PKGα, PKGβ, PRKX, RSK2, and RSK3. At 3 μM or less, AZD 5363 has been reported to inhibit the proliferation of 41 out of 182 solid and hematologic tumor cell lines, demonstrating the greatest sensitivity towards breast cancer derived-cells or those with PIK3CA and/or PTEN mutations. Oral dosing to nude mice bearing BT474c xenografts resulted in antitumor activity, including the reduction of the phosphorylation of PRAS40, GSK3β, and S6 at an EC50 value of ~ 0.1 μM. |
