2. Academic Validation
  3. Design, synthesis and in vitro and in vivo antitumour activity of 3-benzylideneindolin-2-one derivatives, a novel class of small-molecule inhibitors of the MDM2-p53 interaction

Design, synthesis and in vitro and in vivo antitumour activity of 3-benzylideneindolin-2-one derivatives, a novel class of small-molecule inhibitors of the MDM2-p53 interaction

  • Eur J Med Chem. 2014 Jun 23:81:277-88. doi: 10.1016/j.ejmech.2014.05.027.
Guang-hui Zheng 1,  Jia-jia Shen 1,  Yue-chen Zhan 1,  Hong Yi 1,  Si-tu Xue 1,  Zhen Wang 1,  Xing-yue Ji 2,  Zhuo-rong Li 3
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, People's Republic of China.
  • 2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, People's Republic of China. Electronic address: jixingyue@imb.pumc.edu.cn.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, People's Republic of China. Electronic address: l-z-r@263.net.
PMID: 24852275 DOI: 10.1016/j.ejmech.2014.05.027
Abstract

A novel class of small-molecule inhibitors of MDM2-p53 interaction with a (E)-3-benzylideneindolin-2-one scaffold was identified using an integrated virtual screening strategy that combined both pharmacophore- and structure-based approaches. The hit optimisation identified several compounds with more potent activity than the hit compound and the positive drug nutlin-3a, especially compound 1b, which exhibited both the highest binding affinity to MDM2 (Ki = 0.093 μM) and the most potent antiproliferative activity against HCT116 (wild type p53) cells (GI50 = 13.42 μM). Additionally, 1b dose-dependently inhibited tumour growth in BALB/c mice bearing CT26 colon carcinoma, with no visible sign of toxicity. In summary, compound 1b represents a novel and promising lead structure for the development of Anticancer drugs as MDM2-p53 interaction disruptors.

Keywords

Antiproliferative activity; MDM2–p53 interaction; Small-molecule inhibitors.

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