Discovery of <i>N</i>-((3<i>S</i>,4<i>S</i>)-4-(3,4-Difluorophenyl)piperidin-3-yl)-2-fluoro-4-(1-methyl-1<i>H</i>-pyrazol-5-yl)benzamide (Hu7691), a Potent and Selective Akt Inhibitor That Enables Decrease of Cutaneous Toxicity

Abstract

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 <b>2</b> is selected for further optimization for overcoming the disadvantages of compound <b>1</b>, including high Akt2 inhibition and high toxicity against HaCaT keratinocytes. The dihedral angle-based design and molecular dynamics simulation lead to the identification of <b>Hu7691</b> (<b>B5</b>) that achieves a 24-fold selectivity between Akt1 and Akt2. <b>Hu7691</b> 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 <i>in vivo</i> efficacy, the National Medical Products Administration (NMPA) approved the investigational new drug (IND) application of <b>Hu7691</b>.