Target Information

Target General Infomation
Target ID
T00176
Former ID
TTDC00206
Target Name
Ubiquitin-protein ligase E3 Mdm2
Gene Name
MDM2
Synonyms
Double minute 2 protein; Hdm2; MDM2 protein; Oncoprotein Mdm2; P53-binding protein Mdm2; MDM2
Target Type
Clinical Trial
Disease Acute myeloid leukemia [ICD9: 205; ICD10: C92.0]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Hematological malignancies [ICD9: 200-209; ICD10: C81-C86]
Non-small cell lung cancer; Prostate cancer [ICD9:185; ICD10: C33-C34, C61]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Inhibits p53- and p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Functions as a ubiquitin ligase e3, in the presence of e1 and e2, toward p53 and itself. Permits the nuclear export ofp53 and targets it.
BioChemical Class
Carbon-nitrogen ligase
Target Validation
T00176
UniProt ID
Q00987
EC Number
EC 6.3.2.-
Sequence
MCNTNMSVPTDGAVTTSQIPASEQETLVRPKPLLLKLLKSVGAQKDTYTMKEVLFYLGQY
IMTKRLYDEKQQHIVYCSNDLLGDLFGVPSFSVKEHRKIYTMIYRNLVVVNQQESSDSGT
SVSENRCHLEGGSDQKDLVQELQEEKPSSSHLVSRPSTSSRRRAISETEENSDELSGERQ
RKRHKSDSISLSFDESLALCVIREICCERSSSSESTGTPSNPDLDAGVSEHSGDWLDQDS
VSDQFSVEFEVESLDSEDYSLSEEGQELSDEDDEVYQVTVYQAGESDTDSFEEDPEISLA
DYWKCTSCNEMNPPLPSHCNRCWALRENWLPEDKGKDKGEISEKAKLENSTQAEEGFDVP
DCKKTIVNDSRESCVEENDDKITQASQSQESEDYSQPSTSSSIIYSSQEDVKEFEREETQ
DKEESVESSLPLNAIEPCVICQGRPKNGCIVHGKTGHLMACFTCAKKLKKRNKPCPVCRQ
PIQMIVLTYFP
Drugs and Mode of Action
Drug(s) AMG 232 Drug Info Phase 1/2 Cancer [524711]
DS-3032 Drug Info Phase 1 Solid tumours [524327]
JNJ-26854165 Drug Info Phase 1 Non-small cell lung cancer; Prostate cancer [522321]
RG7388 Drug Info Phase 1 Hematological malignancies [525138]
RG7775 Drug Info Phase 1 Acute myeloid leukemia [549548]
Modulator AMG 232 Drug Info [532858]
JNJ-26854165 Drug Info [532478]
RG7388 Drug Info [533203]
Inhibitor DS-3032 Drug Info [525403]
RG7775 Drug Info [550358]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway FoxO signaling pathway
Cell cycle
p53 signaling pathway
Ubiquitin mediated proteolysis
Endocytosis
PI3K-Akt signaling pathway
Thyroid hormone signaling pathway
Epstein-Barr virus infection
Pathways in cancer
Transcriptional misregulation in cancer
Viral carcinogenesis
Proteoglycans in cancer
MicroRNAs in cancer
Glioma
Prostate cancer
Melanoma
Bladder cancer
Chronic myeloid leukemia
PANTHER Pathway Insulin/IGF pathway-protein kinase B signaling cascade
p53 pathway
Ubiquitin proteasome pathway
P53 pathway feedback loops 1
p53 pathway feedback loops 2
Pathway Interaction Database ErbB4 signaling events
p73 transcription factor network
ATR signaling pathway
ATM pathway
Glucocorticoid receptor regulatory network
Sumoylation by RanBP2 regulates transcriptional repression
Direct p53 effectors
Regulation of Androgen receptor activity
Validated transcriptional targets of deltaNp63 isoforms
Aurora A signaling
Validated transcriptional targets of TAp63 isoforms
p53 pathway
Regulation of retinoblastoma protein
Reactome AKT phosphorylates targets in the cytosol
Oxidative Stress Induced Senescence
Oncogene Induced Senescence
Trafficking of AMPA receptors
Constitutive Signaling by AKT1 E17K in Cancer
Stabilization of p53
WikiPathways DNA Damage Response (only ATM dependent)
DNA Damage Response
ErbB Signaling Pathway
Senescence and Autophagy in Cancer
Tryptophan metabolism
G1 to S cell cycle control
Copper homeostasis
Bladder Cancer
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
PIP3 activates AKT signaling
Apoptosis
ATM Signaling Pathway
Retinoblastoma (RB) in Cancer
Integrated Pancreatic Cancer Pathway
Prostate Cancer
Signaling Pathways in Glioblastoma
Integrated Breast Cancer Pathway
Integrated Cancer pathway
Cell Cycle
Cell Cycle Checkpoints
TP53 Network
miRNA Regulation of DNA Damage Response
Androgen receptor signaling pathway
References
Ref 522321ClinicalTrials.gov (NCT00676910) A Research Study of JNJ-26854165 to Determine the Safety and Dose in Patients With Advanced Stage or Refractory Solid Tumors.. U.S. National Institutes of Health.
Ref 524327ClinicalTrials.gov (NCT01877382) A Phase 1 Multiple Ascending Dose Study of DS-3032b, an Oral Murine Double Minute 2 (MDM2) Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas. U.S. National Institutes of Health.
Ref 524711ClinicalTrials.gov (NCT02110355) A Phase 1b/2a Study Evaluating AMG 232 in Metastatic Melanoma. U.S. National Institutes of Health.
Ref 525138ClinicalTrials.gov (NCT02407080) Open Label Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia. U.S. National Institutes of Health.
Ref 549548Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040360)
Ref 525403Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014 Mar;13(3):217-36. doi: 10.1038/nrd4236.
Ref 532478Serdemetan antagonizes the Mdm2-HIF1alpha axis leading to decreased levels of glycolytic enzymes. PLoS One. 2013 Sep 6;8(9):e74741.
Ref 532858Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014 Aug 14;57(15):6332-41.
Ref 533203Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget. 2015 Apr 30;6(12):10207-21.
Ref 550358Phase I clinical trail of RG7775 for treating Acute myelogenous leukemia. Roche.

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