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

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机构： [1]State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China, [2]Department of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China, [3]School of Pharmacy, Chengdu Medical College, Chengdu, China, [4]The First Affiliated Hospital, Chengdu Medical College, Chengdu, China, [5]Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China

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关键词： multitarget drugs histone deacetylase inhibitors MDM2 inhibitors spirooxindole dual inhibitors anticancer

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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.Copyright © 2022 Zhao, Xiong, Chen, Zhu, Xie, Peng, He and Han.

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大类 | 3 区医学

小类 | 3 区肿瘤学

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大类 | 3 区医学

小类 | 3 区肿瘤学

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第一作者机构： [1]State Key Laboratory of Southwestern Chinese Medicine Resources, Hospital of Chengdu University of Traditional Chinese Medicine, School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China,

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