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 re...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-3032 b,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.展开更多
基金supported by the National Natural Science Foundation of China(Nos.81703326 and 81973177 for Bin Yu,and 81773580 for Guochao Liao)China Postdoctoral Science Foundation(Nos.2018M630840 and 2019T120641 for Bin Yu)+2 种基金the Open Fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,China(No.KF-GN-201902 for Bin Yu)Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine(No.2018B030322011 for Guochao Liao,China)Guangdong Province Higher Vocational Colleges and Schools Pearl River Scholar Funded Scheme(No.Guochao Liao,2019,China)
文摘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-3032 b,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.
