Target Information

Target General Information

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

Acute myeloid leukaemia [ICD-11: 2A60]

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.

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BioChemical Class

Acyltransferase

UniProt ID

MDM2_HUMAN

EC Number

EC 2.3.2.27

Sequence

MCNTNMSVPTDGAVTTSQIPASEQETLVRPKPLLLKLLKSVGAQKDTYTMKEVLFYLGQY
IMTKRLYDEKQQHIVYCSNDLLGDLFGVPSFSVKEHRKIYTMIYRNLVVVNQQESSDSGT
SVSENRCHLEGGSDQKDLVQELQEEKPSSSHLVSRPSTSSRRRAISETEENSDELSGERQ
RKRHKSDSISLSFDESLALCVIREICCERSSSSESTGTPSNPDLDAGVSEHSGDWLDQDS
VSDQFSVEFEVESLDSEDYSLSEEGQELSDEDDEVYQVTVYQAGESDTDSFEEDPEISLA
DYWKCTSCNEMNPPLPSHCNRCWALRENWLPEDKGKDKGEISEKAKLENSTQAEEGFDVP
DCKKTIVNDSRESCVEENDDKITQASQSQESEDYSQPSTSSSIIYSSQEDVKEFEREETQ
DKEESVESSLPLNAIEPCVICQGRPKNGCIVHGKTGHLMACFTCAKKLKKRNKPCPVCRQ
PIQMIVLTYFP

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3D Structure

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AlphaFold

HIT2.0 ID

T06PVX

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 10 Clinical Trial Drugs

RG7388

Drug Info

Phase 3

Solid tumour/cancer

[2]

ALRN-6924

Drug Info

Phase 2

Haematological malignancy

[3]

AMG 232

Drug Info

Phase 2

Merkel cell carcinoma

[4]

APG-115

Drug Info

Phase 2

Prolymphocytic leukaemia

[5]

ASTX295

Drug Info

Phase 1/2

Solid tumour/cancer

[6]

BI 907828

Drug Info

Phase 1

Solid tumour/cancer

[7]

DS-3032

Drug Info

Phase 1

Solid tumour/cancer

[8]

HDM201

Drug Info

Phase 1

Haematological malignancy

[9]

JNJ-26854165

Drug Info

Phase 1

Prostate cancer

[10]

RG7775

Drug Info

Phase 1

Acute myeloid leukaemia

[11]

Mode of Action

[+] 3 Modes of Action

Modulator

[+] 3 Modulator drugs

RG7388

Drug Info

[1]

AMG 232

Drug Info

[13]

JNJ-26854165

Drug Info

[17]

Antagonist

[+] 2 Antagonist drugs

ALRN-6924

Drug Info

[3], [12]

ASTX295

Drug Info

[14]

Inhibitor

[+] 6 Inhibitor drugs

APG-115

Drug Info

[3]

BI 907828

Drug Info

[15]

DS-3032

Drug Info

[16]

HDM201

Drug Info

[3]

RG7775

Drug Info

[18]

MI-219

Drug Info

[19]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(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

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 18 KEGG Pathways	+
1	FoxO signaling pathway
2	Cell cycle
3	p53 signaling pathway
4	Ubiquitin mediated proteolysis
5	Endocytosis
6	PI3K-Akt signaling pathway
7	Thyroid hormone signaling pathway
8	Epstein-Barr virus infection
9	Pathways in cancer
10	Transcriptional misregulation in cancer
11	Viral carcinogenesis
12	Proteoglycans in cancer
13	MicroRNAs in cancer
14	Glioma
15	Prostate cancer
16	Melanoma
17	Bladder cancer
18	Chronic myeloid leukemia
Panther Pathway	[+] 5 Panther Pathways	+
1	Insulin/IGF pathway-protein kinase B signaling cascade
2	p53 pathway
3	Ubiquitin proteasome pathway
4	P53 pathway feedback loops 1
5	p53 pathway feedback loops 2
PID Pathway	[+] 13 PID Pathways	+
1	ErbB4 signaling events
2	p73 transcription factor network
3	ATR signaling pathway
4	ATM pathway
5	Glucocorticoid receptor regulatory network
6	Sumoylation by RanBP2 regulates transcriptional repression
7	Direct p53 effectors
8	Regulation of Androgen receptor activity
9	Validated transcriptional targets of deltaNp63 isoforms
10	Aurora A signaling
11	Validated transcriptional targets of TAp63 isoforms
12	p53 pathway
13	Regulation of retinoblastoma protein
Reactome	[+] 6 Reactome Pathways	+
1	AKT phosphorylates targets in the cytosol
2	Oxidative Stress Induced Senescence
3	Oncogene Induced Senescence
4	Trafficking of AMPA receptors
5	Constitutive Signaling by AKT1 E17K in Cancer
6	Stabilization of p53
WikiPathways	[+] 23 WikiPathways	+
1	DNA Damage Response (only ATM dependent)
2	DNA Damage Response
3	ErbB Signaling Pathway
4	Senescence and Autophagy in Cancer
5	Tryptophan metabolism
6	G1 to S cell cycle control
7	Copper homeostasis
8	Bladder Cancer
9	Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
10	PIP3 activates AKT signaling
11	Apoptosis
12	ATM Signaling Pathway
13	Retinoblastoma (RB) in Cancer
14	Integrated Pancreatic Cancer Pathway
15	Prostate Cancer
16	Signaling Pathways in Glioblastoma
17	Integrated Breast Cancer Pathway
18	Integrated Cancer pathway
19	Cell Cycle
20	Cell Cycle Checkpoints
21	TP53 Network
22	miRNA Regulation of DNA Damage Response
23	Androgen receptor signaling pathway

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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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.

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