Huck Bayard R, Mochalkin Igor
Discovery Technologies, Global Research & Development, Merck KGaA, Darmstadt, Germany.
Discovery Technologies, Global Research & Development, Merck KGaA, Darmstadt, Germany.
Bioorg Med Chem Lett. 2017 Jul 1;27(13):2838-2848. doi: 10.1016/j.bmcl.2017.04.090. Epub 2017 Apr 29.
The frequency of PI3K/Akt/mTOR (PAM) Pathway mutations in human cancers sparked interest to determine if the pathway is druggable. The modest clinical benefit observed with mTOR rapalogs (temsirolimus and everolimus) provided further motivation to identify additional nodes of pathway inhibition that lead to improved clinical benefit. Akt is a central signaling node of the PAM pathway and could be an ideal target for improved pathway inhibition. Furthermore, inhibitors of Akt may be especially beneficial in tumors with Akt1 mutations. Recently, multiple ATP-competitive Akt inhibitors have been identified and are currently in clinical development. This review details the medicinal chemistry efforts towards identification of these molecules, highlights relevant preclinical data supporting clinical evaluation, and summarizes current clinical development plans.
PI3K/Akt/mTOR（PAM）信号通路在人类癌症中的突变频率引发了人们对于该通路是否可成药的研究兴趣。mTOR雷帕霉素类似物（坦西莫司和依维莫司）所观察到的适度临床益处，进一步激发了人们去寻找该信号通路中其他可抑制节点，以期带来更大临床获益。Akt是PAM信号通路的核心信号节点，可能是增强该通路抑制效果的理想靶点。此外，Akt抑制剂对于携带Akt1突变的肿瘤可能特别有益。最近，多种ATP竞争性Akt抑制剂已被发现，目前正处于临床开发阶段。本综述详细介绍了为鉴定这些分子所做的药物化学研究工作，重点阐述了支持临床评估的相关临床前数据，并总结了当前的临床开发计划。
