MDM2

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MDM2 antagonists attenuate the senescence-associated secretory phenotype

Processes that have been linked to aging and cancer include an inflammatory milieu driven by senescent cells. Senescent cells lose the ability to divide, essentially irreversibly, and secrete numerous proteases, cytokines and growth factors, termed the senescence-associated secretory phenotype (SASP). Senescent cells that lack p53 tumor suppressor function show an exaggerated SASP, suggesting the SASP is negatively controlled by p53. Here, we show that increased p53 activity caused by small molecule inhibitors of MDM2, which promotes p53 degradation, reduces inflammatory cytokine production by senescent cells. Upon treatment with the MDM2 inhibitors nutlin-3a or MI-63, human cells acquired a senescence-like growth arrest, but the arrest was reversible. Importantly, the inhibitors reduced expression of the signature SASP factors IL-6 and IL-1α by cells made senescent by genotoxic stimuli, and suppressed the ability of senescent fibroblasts to stimulate breast cancer cell aggressiveness. Our findings suggest that MDM2 inhibitors could reduce cancer progression in part by reducing the pro-inflammatory environment created by senescent cells.

SCIENTIFIC STUDIES

  1. A Computational Analysis Of Binding Modes And Conformation Changes Of MDM2 Induced By P53 And Inhibitor Bindings
  2. A Dimethylbromobenzene-Cysteine Stapled Peptide Dual Inhibitor Of The P53-MDM2/Mdmx Interactions
  3. A Gene Signature Composed Of 13 P53 Target Genes Predicts For Response To Nvp-Cgm097, A Novel P53-MDM2 Inhibitor, In Cell Lines And In Human Primary Tumor …
  4. A Novel Orally Active MDM2 Inhibitor (Mi-219) Activates The P53 Pathway And Is Selectively Toxic To Tumor Cells
  5. A novel small molecular inhibitor targets the MDM2-p53 interaction significantly reducing cell viability in both embryonal and alveolar rhabdomyosarcoma cells with wild-type p53
  6. A Novel Small Molecule Inhibitor Of MDM2-P53 (Apg-115) Enhances Radiosensitivity Of Gastric Adenocarcinoma
  7. A Novel Small Molecule Inhibitor Of MDM2-P53 (Apg-115) Has Antitumor Activity In Gastric Adenocarcinoma
  8. A Potent Small-Molecule Inhibitor Of The MDM2–P53 Interaction (Mi-888) Achieved Complete And Durable Tumor Regression In Mice
  9. Abstract 2658: 18F-FLT PET imaging for noninvasive, early assessment of tumor response to MDM2-p53 disruption using a novel MDM2 inhibitor
  10. Abstract 5505: Synergistic anticancer activity of clinical stage, non-genotoxic apoptosis inducing agents RG7388 (MDM2 antagonist) and ABT-199 (GDC-0199, BCL2 inhibitor) in p53 wild-type AML tumor models
  11. Abstract B35: Reactivation Of P53 Signaling In Hepatoblastoma With A Stapled Peptide Dual Inhibitor Of MDM2 And Mdm4
  12. Abstract P1-03-02: Preclinical Efficacy Of A Novel And Potent Inhibitor Of The MDM2-P53 Axis Amg 232 In Er+ Breast Cancer Model
  13. Abstract P3-07-21: Cytotoxic Potential Of The Rg7388 MDM2-P53 Binding Antagonist And The Gsk2830371 Wip1 Inhibitor On Mx-1 And Mcf-7 Human Breast Cancer …
  14. Activation Of P53 By The MDM2 Inhibitor Rg7112 Impairs Thrombopoiesis
  15. Activation of p53 in the tumor microenvironment by MDM2 inhibitor APG-115 synergizes with PD-1 blockade independently of p53 status of tumor cells
  16. Activation of the p53 pathway by the MDM2 inhibitor nutlin-3a overcomes BCL2 overexpression in a preclinical model of diffuse large B-cell lymphoma associated with t(14;18)(q32;q21)
  17. Adaptation Of Cancer Cells From Different Entities To The MDM2 Inhibitor Nutlin-3 Results In The Emergence Of P53-Mutated Multi-Drug-Resistant Cancer Cells
  18. Amelioration Of Radiation Esophagitis By Orally Administered P53/MDM2/Mdm4 Inhibitor (Beb55) Or Gs-Nitroxide
  19. Amg 232, A Small Molecular Inhibitor Of MDM2 Augments Radiation Response In Human Tumors Harboring Wild-Type P53
  20. An Expeditious Synthesis Of The MDM2–P53 Inhibitor Am-8553
  21. Anticancer Effects Of A New Sirt Inhibitor, Mhy2256, Against Human Breast Cancer Mcf-7 Cells Via Regulation Of MDM2-P53 Binding
  22. Atm-Mediated Phosphorylations Inhibit Mdmx/MDM2 Stabilization By Hausp In Favor Of P53 Activation
  23. Binding Of An Inhibitor Of The P53/MDM2 Interaction To MDM2
  24. Catalytic, Enantioselective Synthesis Of Stilbene Cis-Diamines: A Concise Preparation Of (−)-Nutlin-3, A Potent P53/MDM2 Inhibitor
  25. Cellular Pharmacokinetic And Activity Studies With The MDM2-P53 Inhibitor Nutlin-3
  26. Co-Delivery Of P53 And MDM2 Inhibitor Rg7388 Using A Hydroxyl Terminal Pamam Dendrimer Derivative For Synergistic Cancer Therapy
  27. Comparison Of The Antitumor Effects Of An MDM2 Inhibitor, Nutlin-3, In Feline Lymphoma Cell Lines With Or Without P53 Mutation
  28. Conditional Allele Of MDM2 Which Encodes A P53 Inhibitor
  29. Control Of The P53 Protein-MDM2 Inhibitor System Using Nonlinear Kalman Filtering.
  30. Development Of Cell‐Penetrating Peptide‐Based Drug Leads To Inhibit Mdmx: P53 And MDM2: P53 Interactions
  31. Development Of Noncytotoxic Plga Nanoparticles To Improve The Effect Of A New Inhibitor Of P53–MDM2 Interaction
  32. Discovery Of A Nanomolar Inhibitor Of The Human Murine Double Minute 2 (MDM2)− P53 Interaction Through An Integrated, Virtual Database Screening Strategy
  33. Discovery Of A New Inhibitor Of P53/MDM2 Interaction Using A Yeast Target-Based Screening Strategy
  34. Discovery Of A New Small-Molecule Inhibitor Of P53–MDM2 Interaction Using A Yeast-Based Approach
  35. Discovery Of Am-7209, A Potent And Selective 4-Amidobenzoic Acid Inhibitor Of The MDM2–P53 Interaction
  36. Discovery Of Amg 232, A Potent, Selective, And Orally Bioavailable MDM2–P53 Inhibitor In Clinical Development
  37. Discovery Of Amg 232, An Inhibitor Of The MDM2-P53 Interaction: From Lead To A Clinical Candidate
  38. Discovery Of Ds-5272 As A Promising Candidate: A Potent And Orally Active P53–MDM2 Interaction Inhibitor
  39. Discovery Of Rg7388, A Potent And Selective P53–MDM2 Inhibitor In Clinical Development
  40. Discovery Of Scy45, A Natural Small‐Molecule MDM2‐P53 Interaction Inhibitor
  41. Dose And Schedule Determine Distinct Molecular Mechanisms Underlying The Efficacy Of The P53–MDM2 Inhibitor Hdm201
  42. Double-Edged Swords As Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit P53–MDM2 Interaction And The Nf-Κb Pathway
  43. Downregulation Of MDM2 Leads To Anti-Proliferative Effects Through Activation Of P53-Associated Pathway Mediated By Both Dual Inhibitor Mx69 And Mir-548C-3P In …
  44. Efficient Reactivation Of P53 In Cancer Cells By A Dual Mdmx/MDM2 Inhibitor
  45. Fluorescence Polarization Assay And Inhibitor Design For MDM2/P53 Interaction
  46. Front Cover: Discovery Of Scy45, A Natural Small‐Molecule MDM2‐P53 Interaction Inhibitor (C&B 6/2019)
  47. Functional Consequences Of Retro-Inverso Isomerization Of A Miniature Protein Inhibitor Of The P53–MDM2 Interaction
  48. Histone Deacetylase Inhibitor Sodium Butyrate Suppresses Proliferation And Promotes Apoptosis In Osteosarcoma Cells By Regulation Of The MDM2–P53 …
  49. Hoiamide D, A Marine Cyanobacteria-Derived Inhibitor Of P53/MDM2 Interaction
  50. How To Design A Successful P53–MDM2/X Interaction Inhibitor: A Thorough Overview Based On Crystal Structures
  51. Hsp90 Inhibitor Biib021 Enhances Triptolide-Induced Apoptosis Of Human T-Cell Acute Lymphoblastic Leukemia Cells In Vitro Mainly By Disrupting P53-MDM2 …
  52. Human Glioblastoma Multiforme: P53 Reactivation By A Novel MDM2 Inhibitor
  53. I-58 Sylvie Retout Prediction Of Occurrence Of Thrombocytopenia To Select Phase 1B Dose And Dosing Regimen For A Selective Inhibitor Of P53-MDM2 In Patients With …
  54. Identification Of A New P53/MDM2 Inhibitor Motif Inspired By Studies Of Chlorofusin
  55. Identification Of Antipsychotic Drug Fluspirilene As A Potential P53-MDM2 Inhibitor: A Combined Computational And Experimental Study
  56. In Vitro And In Vivo Characterization Of A Novel, Highly Potent P53-MDM2 Inhibitor
  57. In Vitro Characterization Of A Potent P53-MDM2 Inhibitor, Rg7112 In Neuroblastoma Cancer Cell Lines
  58. Inhibition Of S-Adenosylmethionine Decarboxylase By Inhibitor Sam486A Connects Polyamine Metabolism With P53-MDM2-Akt/Protein Kinase B Regulation And …
  59. In-Tether Chiral Center Induced Helical Peptide Modulators Target P53-MDM2/Mdmx And Inhibit Tumor Growth In Stem-Like Cancer Cell
  60. Investigation Of The In-Vivo Cytotoxicity And The In Silico-Prediction Of MDM2-P53 Inhibitor Potential Of Euphorbia Peplus Methanolic Extract In Rats
  61. Life Science: Hoiamide D, A Marine Cyanobacteria-Derived Inhibitor Of P53/MDM2 Interaction
  62. MDM2 Antagonist Can Inhibit Tumor Growth In Hepatocellular Carcinoma With Different Types Of P53 In Vitro
  63. MDM2 Inhibitor Mi-319 In Combination With Cisplatin Is An Effective Treatment For Pancreatic Cancer Independent Of P53 Function
  64. MDM2 Inhibitor Mi-319 In Combination With Cisplatin/Oxaliplatin Is An Effective Treatment For Pancreatic Cancer Independent Of P53 Function
  65. MDM2 Inhibitor Nutlin-3A Induces Apoptosis And Senescence In Cutaneous T-Cell Lymphoma: Role Of P53
  66. MDM2 Inhibitor Nutlin-3A Induces P53-Dependent Apoptosis Via Transcription-Dependent And-Independent Pathways And Overcomes Fludarabine-Resistance In Cll
  67. MDM2 Inhibitor Rg7388 Potently Inhibits Tumors By Activating P53 Pathway In Nasopharyngeal Carcinoma
  68. MDM2 Inhibitor, Nutlin 3A, Induces P53 Dependent Autophagy In Acute Leukemia By Amp Kinase Activation
  69. MDM2-Nfat1 Dual Inhibitor, Ma242: Effective Against Hepatocellular Carcinoma, Independent Of P53
  70. MDM2-P53 Interaction Inhibitor With Cisplatin Enhances Apoptosis In Colon And Prostate Cancer Cells In-Vitro
  71. Mdm4 And MDM2 Cooperate To Inhibit P53 Activity In Proliferating And Quiescent Cells In Vivo
  72. Mdmx Overexpression Prevents P53 Activation By The MDM2 Inhibitor Nutlin
  73. Mechanistic Study Of Nvp-Cgm097: A Potent, Selective And Species Specific Inhibitor Of P53-MDM2
  74. Methyl Elaidate: A Major Compound Of Potential Anticancer Extract Of Moringa Oleifera Seeds Binds With Bax And MDM2 (P53 Inhibitor) In Silico
  75. Mi-63: A Novel Small-Molecule Inhibitor Targets MDM2 And Induces Apoptosis In Embryonal And Alveolar Rhabdomyosarcoma Cells With Wild-Type P53
  76. Network Modeling Of MDM2 Inhibitor-Oxaliplatin Combination Reveals Biological Synergy In Wt-P53 Solid Tumors
  77. New Inhibitor Of The Tap73 Interaction With MDM2 And Mutant P53 With Promising Antitumor Activity Against Neuroblastoma
  78. Non-Linear Feedback Control Of The P53 Protein–MDM2 Inhibitor System Using The Derivative-Free Non-Linear Kalman Filter
  79. Novel MDM2 Inhibitor Sar405838 (Mi-773) Induces P53-Mediated Apoptosis In Neuroblastoma
  80. N-Terminal 130 Amino Acids Of MDM2 Are Sufficient To Inhibit P53-Mediated Transcriptional Activation.
  81. Nutlin-3, The Small-Molecule Inhibitor Of MDM2, Promotes Senescence And Radiosensitises Laryngeal Carcinoma Cells Harbouring Wild-Type P53
  82. Nvp-Cgm097: A Novel P53-MDM2 Inhibitor Exhibiting Potent Antitumor Activity In Mouse Models Of Human Cancer
  83. Nvp-Hdm201: Biochemical And Biophysical Profile Of A Novel Highly Potent And Selective Ppi Inhibitor Of P53-MDM2
  84. Nvp-Hdm201: Cellular And In Vivo Profile Of A Novel Highly Potent And Selective Ppi Inhibitor Of P53-MDM2
  85. On The Biosynthesis Of An Inhibitor Of The P53/MDM2 Interaction
  86. Organocatalytic Diastereoselective [3+ 2] Cyclization Of Mbh Carbonates With Dinucleophiles: Synthesis Of Bicyclic Imidazoline Derivatives That Inhibit MDM2–P53 …
  87. P53 Expression Controls Prostate Cancer Sensitivity To Chemotherapy And The MDM2 Inhibitor Nutlin-3
  88. P53 Mediated Death Of Cells Overexpressing MDM2 By An Inhibitor Of MDM2 Interaction With P53
  89. P709 A Novel MDM2 Inhibitor, Sm13, Induces P53-Dependent Apoptosis In Vascular Smooth Muscle Cell.
  90. Pd-1/Pd-L1 Blockade Enhances MDM2 Inhibitor Activity In P53 Wild-Type Cancers
  91. Pharmacokinetics And Metabolism Of Amg 232, A Novel Orally Bioavailable Inhibitor Of The MDM2–P53 Interaction, In Rats, Dogs And Monkeys: In Vitro–In Vivo …
  92. Phase 1 Study Of The MDM2 Inhibitor Amg 232 In Patients With Advanced P53 Wild-Type Solid Tumors Or Multiple Myeloma
  93. Phase 1 Study Of The P53-MDM2 Inhibitor Amg 232 Combined With Trametinib Plus Dabrafenib Or Trametinib In Patients (Pts) With Tp53 Wild Type (Tp53Wt) Metastatic …
  94. Preclinical Characterization Of Mi-219, A Novel, Potent And Orally Active Small Molecule Inhibitor Of The MDM2-P53 Interaction.
  95. Protoporphyrin Ix Is A Dual Inhibitor Of P53/MDM2 And P53/Mdm4 Interactions And Induces Apoptosis In B-Cell Chronic Lymphocytic Leukemia Cells
  96. Radiosensitization Of Wildtype P53 Cancer Cells By The MDM2-Inhibitor Pxn727 Is Associated With Altered Heat Shock Protein 70 (Hsp70) Levels
  97. Reactivation Of P53 By MDM2 Inhibitor Mi-77301 For The Treatment Of Endocrine-Resistant Breast Cancer
  98. Reactivation Of The P53 Pathway By MDM2 Inhibitor Nutlin-3: Application In Photochemical Internalisation (Pci)
  99. Recombinant Dual-Target MDM2/Mdmx Inhibitor Reverses Doxorubicin Resistance Through Activation Of The Tab1/Tak1/P38 Mapk Pathway In Wild-Type P53 …
  100. Retraction Of “Efficient Reactivation Of P53 In Cancer Cells By A Dual Mdmx/MDM2 Inhibitor”
  101. Sar405838: A Novel And Potent Inhibitor Of The MDM2: P53 Axis For The Treatment Of Dedifferentiated Liposarcoma
  102. Sar405838: An Optimized Inhibitor Of MDM2–P53 Interaction That Induces Complete And Durable Tumor Regression
  103. Sf1126, A Novel Pan-Pi3K Inhibitor, Inhibits Activation Of MDM2 And Increases Sensitivity To Doxorubicin In Wild Type P53 Neuroblastoma Cell Lines
  104. Small Molecule Inhibitor Of MDM2 Induces P53-Dependent Hmgb1 Secretion Followed By Apoptosis In Cancer Cells And Incomplete Senescence In Normal Fibroblasts
  105. Solid-Phase Synthesis Of The Cyclic Peptide Portion Of Chlorofusin, An Inhibitor Of P53-MDM2 Interactions
  106. Stapled Α− Helical Peptide Drug Development: A Potent Dual Inhibitor Of MDM2 And Mdmx For P53-Dependent Cancer Therapy
  107. Structural Studies On A P53-MDM2 Inhibitor
  108. Superior Anti-Tumor Activity Of The MDM2 Antagonist Idasanutlin And The Bcl-2 Inhibitor Venetoclax In P53 Wild-Type Acute Myeloid Leukemia Models
  109. Surface Plasmon Resonance And Cytotoxicity Assays Of Drug Efficacies Predicted Computationally To Inhibit P53/MDM2 Interaction
  110. Synergistic Effect Of Combination Treatment With Mi-219, A Small Molecule Inhibitor Of The MDM2-P53 Interaction, And Kinase Inhibitors Or Chemotherapeutic Agents.
  111. Targeting P53-MDM2 Interaction Using A Potent MDM2 Inhibitor To Overcome Cisplatin Resistance In Head And Neck Squamous Cell Carcinoma
  112. Targeting The P53 Tumor Suppressor Activity In Glioblastomas Using Small Molecule MDM2-Inhibitor
  113. Temporal Activation Of P53 By A Specific MDM2 Inhibitor Is Selectively Toxic To Tumors And Leads To Complete Tumor Growth Inhibition
  114. The Cellular P53 Inhibitor MDM2 And The Growth Factor Receptor Flt3 As Biomarkers For Treatment Responses To The MDM2-Inhibitor Idasanutlin And The Mek1 Inhibitor …
  115. The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by MDM2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML
  116. The Hdm2 (MDM2) Inhibitor Nvp-Cgm097 Inhibits Tumor Cell Proliferation And Shows Additive Effects With 5-Fluorouracil On The P53-P21-Rb-E2F1 Cascade In The …
  117. The Human Oncoprotein MDM2 Uses Distinct Strategies To Inhibit Transcriptional Activation Mediated By The Wild-Type P53 And Its Tumor-Derived Mutants
  118. The Hydrophobically-Tagged MDM2–P53 Interaction Inhibitor Nutlin-3A-Ht Is More Potent Against Tumor Cells Than Nutlin-3A
  119. The Isolation, Total Synthesis And Structure Elucidation Of Chlorofusin, A Natural Product Inhibitor Of The P53–MDM2 Protein–Protein Interaction
  120. The MDM2 Inhibitor Amg 232 Demonstrates Robust Antitumor Efficacy And Potentiates The Activity Of P53-Inducing Cytotoxic Agents
  121. The MDM2 Inhibitor, Nutlin–3A, Is Capable Of Inhibiting Endothelial Cell Proliferation Via P53 Mediated Apoptosis
  122. The MDM2 Small-Molecule Inhibitor Rg7388 Leads To Potent Tumor Inhibition In P53 Wild-Type Neuroblastoma
  123. The MDM2-Inhibitor Nutlin-3 Synergizes With Cisplatin To Induce P53 Dependent Tumor Cell Apoptosis In Non-Small Cell Lung Cancer
  124. The Nedd8 Inhibitor Mln4924 Increases The Size Of The Nucleolus And Activates P53 Through The Ribosomal-MDM2 Pathway
  125. The P53 Inhibitor MDM2 Facilitates Sonic Hedgehog-Mediated Tumorigenesis And Influences Cerebellar Foliation
  126. The P53 Tumor Suppressor Protein Does Not Regulate Expression Of Its Own Inhibitor, MDM2, Except Under Conditions Of Stress
  127. The P53-MDM2 Interaction: Predicting Helix Mimetic Side-Chain Modifications Likely To Increase Inhibitor Affinity
  128. The Pre-Clinical Development Of MDM2 Inhibitors In Chronic Lymphocytic Leukemia Uncovers A Central Role For P53 Status In Sensitivity To MDM2 Inhibitor-Mediated …
  129. The Role Of P53 And P21 In Cancer Therapy With MDM2 Inhibitor.
  130. Use Of A Retroinverso P53 Peptide As An Inhibitor Of MDM2

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