首页|Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy:advances and perspectives

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy:advances and perspectives

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Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers.Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996,SAR405838,NVP-CGM097,MK-8242,RG7112,RG7388,DS-3032b,and AMG232 currently undergo clinical evaluation for cancer therapy.This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera (PROTAC) degraders with a particular focus on how these inhibitors or degraders are identified from starting points,strategies employed,structure-activity relationship (SAR) studies,binding modes or co-crystal structures,biochemical data,mechanistic studies,and preclinical/clinical studies.Moreover,we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition,acquired resistance and toxicity of P53 activation as well as future directions.

MDM2/X-P53 interactionMDM2/X inhibitorsPROTAC degradersCancer therapy

Yuan Fang、Guochao Liao、Bin Yu

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Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China

School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China

State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaChina Postdoctoral Science FoundationChina Postdoctoral Science FoundationOpen Fund of State Key Laboratory of Pharmaceutical

Nos8170332681973177 for Bin Yu81773580 for Guochao LiaoNos2018M6308402019T120641 for Bin Yu

2020

药学学报(英文版)

药学学报(英文版)

CSTPCDCSCDSCI
ISSN：
年,卷(期)：2020.10(7)
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