Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT08GJW)

• DTT Name: Ubiquitin-protein ligase E3 Mdm2 (MDM2)
• Synonyms: RING-type E3 ubiquitin transferase Mdm2; P53-binding protein Mdm2; Oncoprotein Mdm2; MDM2 protein; Hdm2; E3 ubiquitin-protein ligase Mdm2; Double minute 2 protein
• Gene Name: MDM2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Acyltransferase
• UniProt ID: MDM2_HUMAN
• TTD ID: T00176
• EC Number: EC 2.3.2.27
• Sequence:
  MCNTNMSVPTDGAVTTSQIPASEQETLVRPKPLLLKLLKSVGAQKDTYTMKEVLFYLGQY
  IMTKRLYDEKQQHIVYCSNDLLGDLFGVPSFSVKEHRKIYTMIYRNLVVVNQQESSDSGT
  SVSENRCHLEGGSDQKDLVQELQEEKPSSSHLVSRPSTSSRRRAISETEENSDELSGERQ
  RKRHKSDSISLSFDESLALCVIREICCERSSSSESTGTPSNPDLDAGVSEHSGDWLDQDS
  VSDQFSVEFEVESLDSEDYSLSEEGQELSDEDDEVYQVTVYQAGESDTDSFEEDPEISLA
  DYWKCTSCNEMNPPLPSHCNRCWALRENWLPEDKGKDKGEISEKAKLENSTQAEEGFDVP
  DCKKTIVNDSRESCVEENDDKITQASQSQESEDYSQPSTSSSIIYSSQEDVKEFEREETQ
  DKEESVESSLPLNAIEPCVICQGRPKNGCIVHGKTGHLMACFTCAKKLKKRNKPCPVCRQ
  PIQMIVLTYFP
• Function: Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation. Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells. Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis. E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome.
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  Cell cycle (hsa04110)
  p53 signaling pathway (hsa04115)
  Ubiquitin mediated proteolysis (hsa04120)
  Endocytosis (hsa04144)
  PI3K-Akt signaling pathway (hsa04151)
  Thyroid hormone signaling pathway (hsa04919)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
  Bladder cancer (hsa05219)
  Chronic myeloid leukemia (hsa05220)
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Oncogene Induced Senescence (R-HSA-2559585)
  Trafficking of AMPA receptors (R-HSA-399719)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  Stabilization of p53 (R-HSA-69541)
  AKT phosphorylates targets in the cytosol (R-HSA-198323)

Molecular Interaction Atlas (MIA) of This DTT

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RG7388	DMF5GZI	Acute myeloid leukaemia	2A60	Phase 3	[1]
ALRN-6924	DMLBWT1	Haematological malignancy	2B33.Y	Phase 2	[2]
AMG 232	DM65PTO	Merkel cell carcinoma	2C34	Phase 2	[3]
APG-115	DMIFA0L	Prolymphocytic leukaemia	2A82.1	Phase 2	[2]
ASTX295	DM9EM5G	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[4]
BI 907828	DM2Z4YQ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
DS-3032	DMA2B5Y	Haematological malignancy	2B33.Y	Phase 1	[6]
HDM201	DMVRTCW	Haematological malignancy	2B33.Y	Phase 1	[2]
JNJ-26854165	DMNSJ3C	Non-small-cell lung cancer	2C25.Y	Phase 1	[7]
RG7775	DMXBS6U	Acute myeloid leukaemia	2A60	Phase 1	[8]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MI-219	DM196LK	Triple negative breast cancer	2C60-2C65	Investigative	[9]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	1.19E-04	0.05	0.16
Lung cancer	2C82	Lung tissue	8.31E-13	0.12	0.44
Acute myelocytic leukaemia	2C82	Bone marrow	1.28E-04	0.09	0.5

References

• [1] Pre-clinical evaluation of the MDM2-p53 antagonist RG7388 alone and in combination with chemotherapy in neuroblastoma. Oncotarget. 2015 Apr 30;6(12):10207-21.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014 Aug 14;57(15):6332-41.
• [4] Clinical pipeline report, company report or official report of Astex Pharmaceuticals.
• [5] MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020 Nov;34(11):2858-2874.
• [6] Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014 Mar;13(3):217-36.
• [7] Serdemetan antagonizes the Mdm2-HIF1alpha axis leading to decreased levels of glycolytic enzymes. PLoS One. 2013 Sep 6;8(9):e74741.
• [8] Phase I clinical trail of RG7775 for treating Acute myelogenous leukemia. Roche.
• [9] MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy. Oncogene. 2011 Jan 6;30(1):117-26.