2. Academic Validation
  3. Discovery of pyrazole-thiophene derivatives as highly Potent, orally active Akt inhibitors

Discovery of pyrazole-thiophene derivatives as highly Potent, orally active Akt inhibitors

  • Eur J Med Chem. 2019 Oct 15:180:72-85. doi: 10.1016/j.ejmech.2019.07.017.
Wenhu Zhan 1,  Jinxin Che 1,  Lei Xu 2,  Yizhe Wu 1,  Xiaobei Hu 2,  Yubo Zhou 2,  Gang Cheng 3,  Yongzhou Hu 1,  Xiaowu Dong 4,  Jia Li 5
Affiliations

Affiliations

  • 1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 3 College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, 311402, PR China.
  • 4 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: dongxw@zju.edu.cn.
  • 5 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: jli@simm.ac.cn.
PMID: 31301565 DOI: 10.1016/j.ejmech.2019.07.017
Abstract

A series of pyrazole-thiophene derivatives exhibiting good Akt inhibitory activities were obtained on the basis of conformational restriction strategy, leading to the discovery of compound 1d and 1o which showed excellent in vitro antitumor effect against a variety of hematologic Cancer cells and their potential of inducing Apoptosis, blocking the cell cycles at S phase and significantly inhibiting the phosphorylation of downstream biomarkers of Akt kinase of Cancer cells. Amongst, compound 1o also exhibited good PK profiles and inhibited about 40% tumor growth in MM1S xenograft model. Compound 1o might be a potential candidate for further development.

Keywords

Akt inhibitor; Antitumor; Pyrazole-thiophene derivatives.

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