哈卡特
化学
蛋白激酶B
AKT1型
药理学
体内
AKT2型
细胞生长
癌症研究
细胞凋亡
体外
生物化学
医学
生物
生物技术
作者
Yongzhou Hu,Xiaoyang Dai,Jian Gao,Sheng Haichao,Wenhu Zhan,Yang Lu,Dan Li,Zizheng Gao,Zegao Jin,Binhui Chen,Peihua Luo,Bo Yang,Yongzhou Hu,Qiaojun He,Qinjie Weng,Xiaowu Dong
标识
DOI:10.1021/acs.jmedchem.1c00815
摘要
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.
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