Discovery of spirooxindole-derived small-molecule compounds as novel HDAC/MDM2 dual inhibitors and investigation of their anticancer activity

Simultaneous inhibition of more than one target is considered to be a novel strategy in cancer therapy. Owing to the importance of histone deacetylases (HDACs) and p53-murine double minute 2 (MDM2) interaction in tumor development and their synergistic effects, a series of MDM2/HDAC bifunctional sma...

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Published inFrontiers in oncology Vol. 12; p. 972372
Main Authors Zhao, Qian, Xiong, Shan-Shan, Chen, Can, Zhu, Hong-Ping, Xie, Xin, Peng, Cheng, He, Gu, Han, Bo
Format Journal Article
LanguageEnglish
Published Frontiers Media S.A 04.08.2022
Subjects
anticancer
dual inhibitors
histone deacetylase inhibitors
MDM2 inhibitors
multitarget drugs
Oncology
spirooxindole
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Summary:Simultaneous inhibition of more than one target is considered to be a novel strategy in cancer therapy. Owing to the importance of histone deacetylases (HDACs) and p53-murine double minute 2 (MDM2) interaction in tumor development and their synergistic effects, a series of MDM2/HDAC bifunctional small-molecule inhibitors were rationally designed and synthesized by incorporating an HDAC pharmacophore into spirooxindole skeletons. These compounds exhibited good inhibitory activities against both targets. In particular, compound 11b was demonstrated to be most potent for MDM2 and HDAC, reaching the enzyme inhibition of 68% and 79%, respectively. Compound 11b also showed efficient antiproliferative activity towards MCF-7 cells with better potency than the reference drug SAHA and Nutlin-3. Furthermore, western blot analysis revealed that compound 11b increased the expression of p53 and Ac-H4 in MCF-7 cells in a dose-dependent manner. Our results indicate that dual inhibition of HDAC and MDM2 may provide a novel and efficient strategy for the discovery of antitumor drug in the future.
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Edited by: Leilei Fu, Southwest Jiaotong University, China
Reviewed by: Xiaoxiao Huang, Shenyang Pharmaceutical University, China; Chun-Han Chen, Taipei Medical University, Taiwan; Feng Gao, Southwest Jiaotong University, China
These authors have contributed equally to this work
This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology
ISSN:2234-943X
2234-943X
DOI:10.3389/fonc.2022.972372