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

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

  • J Med Chem. 2021 Aug 26;64(16):12163-12180. doi: 10.1021/acs.jmedchem.1c00815.
Jinxin Che 1,  Xiaoyang Dai 2,  Jian Gao 1,  Haichao Sheng 1,  Wenhu Zhan 1,  Yang Lu 1,  Dan Li 1,  Zizheng Gao 3,  Zegao Jin 1,  Binhui Chen 1,  Peihua Luo 3,  Bo Yang 1 3,  Yongzhou Hu 1,  Qiaojun He 1 2 3 4 5,  Qinjie Weng 2 3 4,  Xiaowu Dong 1 4 5
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
  • 2 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
  • 3 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
  • 4 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, P. R. China.
  • 5 Cancer Center, Zhejiang University, Hangzhou 310058, P. R. China.
PMID: 34375113 DOI: 10.1021/acs.jmedchem.1c00815
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 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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