In the past decade,the p53-MDM2 protein-protein interaction by small molecules has been confirmed as a successful strategy for cancer therapy.In our previous work,pyrrolo[3,4-c]pyrazol-6（1H）-ones were found to be po...In the past decade,the p53-MDM2 protein-protein interaction by small molecules has been confirmed as a successful strategy for cancer therapy.In our previous work,pyrrolo[3,4-c]pyrazol-6（1H）-ones were found to be potent p53-MDM2 inhibitors.Further optimization and structure-activity relationship studies were described in the present work.The result revealed that benzyl group on position N1 of imidazole and bromine on C4-phenyl of pyrrolidone showed higher inhibitory activities.In vitro antiproliferative assay demonstrated the potent p53-MDM2 inhibitor 5c with 4-fold selectivity for U2 OS and Saos-2 cells.These data indicated that 4,5-dihydropyrrolo[3,4-c]pyrazol-6（1H）-one moiety is a valuable scaffold for further development of p53-MDM2 inhibitors.展开更多
Murine double minute 2(MDM2)plays an essential role in the cell cycle,apoptosis,DNA repair,and oncogene activation through p53-dependent and p53-independent signaling pathways.Several preclinical studies have shown th...Murine double minute 2(MDM2)plays an essential role in the cell cycle,apoptosis,DNA repair,and oncogene activation through p53-dependent and p53-independent signaling pathways.Several preclinical studies have shown that MDM2 is involved in tumor immune evasion.Therefore,MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention.In recent years,im-mune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic.Howev-er,the effectiveness of a single agent is only approximately 20%-40%,which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins.Here,we reviewed the role of MDM2 in regulating the immune microenvironment,tumor immune evasion,and hyperprogression during immunotherapy.In addition,we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tu-mors with MDM2 overexpression or amplification.The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.展开更多
Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53.Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models.The tissuespecific deletion of Mdm2 in...Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53.Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models.The tissuespecific deletion of Mdm2 induces p53-dependent apoptosis,whereas the deletion of Mdm4 induces both p53-dependent apoptosis and cell cycle arrest.Compared to Mdm4 deletion,Mdm2 deletion causes more severe phenotypic defects.Disrupting the Mdm2 and Mdm4 interaction using knockin mice models causes embryonic lethality that can be completely rescued by the concomitant loss of p53,suggesting that Mdm2 and Mdm4 heterodimerization is critical to inhibit p53 activity during embryogenesis.Overexpression of Mdm2 and Mdm4 in mice induces spontaneous tumorigenesis,which clearly indicates that Mdm2 and Mdm4 are bona fide oncogenes.Studies from these mouse models strongly suggest that blocking Mdm2and Mdm4-mediated p53 inhibition is an appealing therapeutic strategy for cancer patients with wild-type p53 alleles.展开更多
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 in part by the National Natural Science Foundation of China (Nos. 81373331 and 81502978)the Bio-Pharmaceutical Project of Science and Technology of Shanghai (No. 14431902300)Youth grant of Second Military Medical University (No. 2014QN08)
文摘In the past decade,the p53-MDM2 protein-protein interaction by small molecules has been confirmed as a successful strategy for cancer therapy.In our previous work,pyrrolo[3,4-c]pyrazol-6（1H）-ones were found to be potent p53-MDM2 inhibitors.Further optimization and structure-activity relationship studies were described in the present work.The result revealed that benzyl group on position N1 of imidazole and bromine on C4-phenyl of pyrrolidone showed higher inhibitory activities.In vitro antiproliferative assay demonstrated the potent p53-MDM2 inhibitor 5c with 4-fold selectivity for U2 OS and Saos-2 cells.These data indicated that 4,5-dihydropyrrolo[3,4-c]pyrazol-6（1H）-one moiety is a valuable scaffold for further development of p53-MDM2 inhibitors.
基金supported by the National Natural Science Foundation of China (No.82202869,82260491,82160459)Jiangxi Province"Double Thousand Program" (China) (No.jxsq 2023201108)+1 种基金China Postdoctoral Science Foundation (No.338937)the Jiangxi Provincial Natural Science Foundation (China) (No.20232ACB206044).
文摘Murine double minute 2(MDM2)plays an essential role in the cell cycle,apoptosis,DNA repair,and oncogene activation through p53-dependent and p53-independent signaling pathways.Several preclinical studies have shown that MDM2 is involved in tumor immune evasion.Therefore,MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention.In recent years,im-mune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic.Howev-er,the effectiveness of a single agent is only approximately 20%-40%,which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins.Here,we reviewed the role of MDM2 in regulating the immune microenvironment,tumor immune evasion,and hyperprogression during immunotherapy.In addition,we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tu-mors with MDM2 overexpression or amplification.The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.
文摘Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53.Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models.The tissuespecific deletion of Mdm2 induces p53-dependent apoptosis,whereas the deletion of Mdm4 induces both p53-dependent apoptosis and cell cycle arrest.Compared to Mdm4 deletion,Mdm2 deletion causes more severe phenotypic defects.Disrupting the Mdm2 and Mdm4 interaction using knockin mice models causes embryonic lethality that can be completely rescued by the concomitant loss of p53,suggesting that Mdm2 and Mdm4 heterodimerization is critical to inhibit p53 activity during embryogenesis.Overexpression of Mdm2 and Mdm4 in mice induces spontaneous tumorigenesis,which clearly indicates that Mdm2 and Mdm4 are bona fide oncogenes.Studies from these mouse models strongly suggest that blocking Mdm2and Mdm4-mediated p53 inhibition is an appealing therapeutic strategy for cancer patients with wild-type p53 alleles.
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.
