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

Guang-hui Zheng; Jia-jia Shen; Yue-chen Zhan; Hong Yi; Si-tu Xue; Zhen Wang; Xing-yue Ji; Zhuo-rong Li

doi:10.1016/j.ejmech.2014.05.027

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. Epub 2014 May 9.

Authors

Guang-hui Zheng¹, Jia-jia Shen¹, Yue-chen Zhan¹, Hong Yi¹, Si-tu Xue¹, Zhen Wang¹, Xing-yue Ji², Zhuo-rong Li³

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Cycle / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
Mice
Mice, Inbred BALB C
Models, Molecular
Molecular Structure
Molecular Weight
Neoplasms, Experimental / drug therapy*
Neoplasms, Experimental / pathology
Protein Binding / drug effects
Proto-Oncogene Proteins c-mdm2 / metabolism*
Structure-Activity Relationship
Tumor Suppressor Protein p53 / metabolism*

Substances

Antineoplastic Agents
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2