Discovery of N‑((3S,4S)‑4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl‑1H‑pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective
Akt Inhibitor That Enables Decrease of Cutaneous Toxicity
posted on 2021-08-10, 16:56authored byJinxin Che, Xiaoyang Dai, Jian Gao, Haichao Sheng, Wenhu Zhan, Yang Lu, Dan Li, Zizheng Gao, Zegao Jin, Binhui Chen, Peihua Luo, Bo Yang, Yongzhou Hu, Qiaojun He, Qinjie Weng, Xiaowu Dong
Rash is one of the primary dose-limiting toxicities of Akt (protein
kinase B) inhibitors in clinical trials. Here, we demonstrate the
inhibition of Akt2 isozyme may be a driver for keratinocyte apoptosis,
which promotes us to search for new selective Akt inhibitors with
an improved cutaneous safety property. According to our previous research,
compound 2 is selected for further optimization for overcoming
the disadvantages of compound 1, including high Akt2
inhibition and high toxicity against HaCaT keratinocytes. The dihedral
angle-based design and molecular dynamics simulation lead to the identification
of Hu7691 (B5) that achieves a 24-fold selectivity
between Akt1 and Akt2. Hu7691 exhibits low activity in
inducing HaCaT apoptosis, promising kinase selectivity, and excellent
anticancer cell proliferation potencies. Based on the superior results
of safety property, pharmacokinetic profile, and in vivo efficacy, the National Medical Products Administration (NMPA) approved
the investigational new drug (IND) application of Hu7691.