Target Information
Target General Information | Top | |||||
---|---|---|---|---|---|---|
Target ID |
T00176
(Former ID: TTDC00206)
|
|||||
Target 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
|
|||||
Target Type |
Clinical trial target
|
[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Acute myeloid leukaemia [ICD-11: 2A60] | |||||
2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
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.
Click to Show/Hide
|
|||||
BioChemical Class |
Acyltransferase
|
|||||
UniProt ID | ||||||
EC Number |
EC 2.3.2.27
|
|||||
Sequence |
MCNTNMSVPTDGAVTTSQIPASEQETLVRPKPLLLKLLKSVGAQKDTYTMKEVLFYLGQY
IMTKRLYDEKQQHIVYCSNDLLGDLFGVPSFSVKEHRKIYTMIYRNLVVVNQQESSDSGT SVSENRCHLEGGSDQKDLVQELQEEKPSSSHLVSRPSTSSRRRAISETEENSDELSGERQ RKRHKSDSISLSFDESLALCVIREICCERSSSSESTGTPSNPDLDAGVSEHSGDWLDQDS VSDQFSVEFEVESLDSEDYSLSEEGQELSDEDDEVYQVTVYQAGESDTDSFEEDPEISLA DYWKCTSCNEMNPPLPSHCNRCWALRENWLPEDKGKDKGEISEKAKLENSTQAEEGFDVP DCKKTIVNDSRESCVEENDDKITQASQSQESEDYSQPSTSSSIIYSSQEDVKEFEREETQ DKEESVESSLPLNAIEPCVICQGRPKNGCIVHGKTGHLMACFTCAKKLKKRNKPCPVCRQ PIQMIVLTYFP Click to Show/Hide
|
|||||
3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T06PVX |
Drugs and Modes of Action | Top | |||||
---|---|---|---|---|---|---|
Clinical Trial Drug(s) | [+] 10 Clinical Trial Drugs | + | ||||
1 | RG7388 | Drug Info | Phase 3 | Solid tumour/cancer | [2] | |
2 | ALRN-6924 | Drug Info | Phase 2 | Haematological malignancy | [3] | |
3 | AMG 232 | Drug Info | Phase 2 | Merkel cell carcinoma | [4] | |
4 | APG-115 | Drug Info | Phase 2 | Prolymphocytic leukaemia | [5] | |
5 | ASTX295 | Drug Info | Phase 1/2 | Solid tumour/cancer | [6] | |
6 | BI 907828 | Drug Info | Phase 1 | Solid tumour/cancer | [7] | |
7 | DS-3032 | Drug Info | Phase 1 | Solid tumour/cancer | [8] | |
8 | HDM201 | Drug Info | Phase 1 | Haematological malignancy | [9] | |
9 | JNJ-26854165 | Drug Info | Phase 1 | Prostate cancer | [10] | |
10 | RG7775 | Drug Info | Phase 1 | Acute myeloid leukaemia | [11] | |
Mode of Action | [+] 3 Modes of Action | + | ||||
Modulator | [+] 3 Modulator drugs | + | ||||
1 | RG7388 | Drug Info | [1] | |||
2 | AMG 232 | Drug Info | [13] | |||
3 | JNJ-26854165 | Drug Info | [17] | |||
Antagonist | [+] 2 Antagonist drugs | + | ||||
1 | ALRN-6924 | Drug Info | [3], [12] | |||
2 | ASTX295 | Drug Info | [14] | |||
Inhibitor | [+] 6 Inhibitor drugs | + | ||||
1 | APG-115 | Drug Info | [3] | |||
2 | BI 907828 | Drug Info | [15] | |||
3 | DS-3032 | Drug Info | [16] | |||
4 | HDM201 | Drug Info | [3] | |||
5 | RG7775 | Drug Info | [18] | |||
6 | MI-219 | Drug Info | [19] |
Chemical Structure based Activity Landscape of Target | Top |
---|---|
Drug Property Profile of Target | Top | |
---|---|---|
(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
|
||
(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
|
||
(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
|
||
"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Target Poor or Non Binders | Top | |||||
---|---|---|---|---|---|---|
Target Poor or Non Binders |
Target Regulators | Top | |||||
---|---|---|---|---|---|---|
Target-regulating microRNAs | ||||||
Target-regulating Transcription Factors | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
---|---|---|---|---|---|---|
Target Expression Profile (TEP) |
Target-Related Models and Studies | Top | |||||
---|---|---|---|---|---|---|
Target Validation |
References | Top | |||||
---|---|---|---|---|---|---|
REF 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. | |||||
REF 2 | Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.Nat Rev Drug Discov. 2016 Aug;15(8):533-50. | |||||
REF 3 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 4 | ClinicalTrials.gov (NCT03787602) This Study Evaluates KRT-232, a Novel Oral Small Molecule Inhibitor of MDM2, for the Treatment of Patients With (p53WT) Merkel Cell Carcinoma Who Have Failed Anti-PD-1/ PD-L1 Immunotherapy. U.S. National Institutes of Health. | |||||
REF 5 | ClinicalTrials.gov (NCT04496349) A Study Evaluating APG-115 as a Single Agent or in Combination With APG-2575 in Subjects With T-PLL. U.S. National Institutes of Health. | |||||
REF 6 | ClinicalTrials.gov (NCT03975387) Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53. U.S. National Institutes of Health. | |||||
REF 7 | ClinicalTrials.gov (NCT03449381) This Study Aims to Find the Best Dose of BI 907828 in Patients With Different Types of Advanced Cancer (Solid Tumors). U.S. National Institutes of Health. | |||||
REF 8 | ClinicalTrials.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 9 | ClinicalTrials.gov (NCT02143635) Study to Determine and Evaluate a Safe and Tolerated Dose of HDM201 in Patients With Selected Advanced Tumors That Are TP53wt. U.S. National Institutes of Health. | |||||
REF 10 | ClinicalTrials.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 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800040360) | |||||
REF 12 | Anti-ageing pipeline starts to mature.Nat Rev Drug Discov. 2018 Sep;17(9):609-612. | |||||
REF 13 | Discovery of a small molecule MDM2 inhibitor (AMG 232) for treating cancer. J Med Chem. 2014 Aug 14;57(15):6332-41. | |||||
REF 14 | Clinical pipeline report, company report or official report of Astex Pharmaceuticals. | |||||
REF 15 | MDM2 inhibition: an important step forward in cancer therapy. Leukemia. 2020 Nov;34(11):2858-2874. | |||||
REF 16 | Drugging the p53 pathway: understanding the route to clinical efficacy. Nat Rev Drug Discov. 2014 Mar;13(3):217-36. | |||||
REF 17 | Serdemetan antagonizes the Mdm2-HIF1alpha axis leading to decreased levels of glycolytic enzymes. PLoS One. 2013 Sep 6;8(9):e74741. | |||||
REF 18 | Phase I clinical trail of RG7775 for treating Acute myelogenous leukemia. Roche. | |||||
REF 19 | MI-219-zinc combination: a new paradigm in MDM2 inhibitor-based therapy. Oncogene. 2011 Jan 6;30(1):117-26. |
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.