Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOVXARF)

• DOT Name: E3 ubiquitin-protein ligase Mdm2 (MDM2)
• Synonyms: EC 2.3.2.27; Double minute 2 protein; Hdm2; Oncoprotein Mdm2; RING-type E3 ubiquitin transferase Mdm2; p53-binding protein Mdm2
• Gene Name: MDM2
• Related Disease: Lessel-kubisch syndrome
• UniProt ID: MDM2_HUMAN
• PDB ID: 1RV1 ; 1T4E ; 1T4F ; 1YCR ; 1Z1M ; 2AXI ; 2C6A ; 2C6B ; 2F1Y ; 2FOP ; 2GV2 ; 2HDP ; 2LZG ; 2M86 ; 2MPS ; 2RUH ; 2VJE ; 2VJF ; 3EQS ; 3G03 ; 3IUX ; 3IWY ; 3JZK ; 3JZR ; 3JZS ; 3LBK ; 3LBL ; 3LNJ ; 3LNZ ; 3MQS ; 3TJ2 ; 3TPX ; 3TU1 ; 3V3B ; 3VBG ; 3VZV ; 3W69 ; 4DIJ ; 4ERE ; 4ERF ; 4HBM ; 4HFZ ; 4HG7 ; 4JV7 ; 4JV9 ; 4JVE ; 4JVR ; 4JWR ; 4MDN ; 4MDQ ; 4OAS ; 4OBA ; 4OCC ; 4ODE ; 4ODF ; 4OGN ; 4OGT ; 4OGV ; 4OQ3 ; 4QO4 ; 4QOC ; 4UD7 ; 4UE1 ; 4UMN ; 4WT2 ; 4XXB ; 4ZFI ; 4ZGK ; 4ZYC ; 4ZYF ; 4ZYI ; 5AFG ; 5C5A ; 5HMH ; 5HMI ; 5HMK ; 5J7F ; 5J7G ; 5LAV ; 5LAW ; 5LAY ; 5LAZ ; 5LN2 ; 5MNJ ; 5OAI ; 5OC8 ; 5SWK ; 5TRF ; 5UMM ; 5VK0 ; 5WTS ; 5XXK ; 5Z02 ; 5ZXF ; 6AAW ; 6GGN ; 6H22 ; 6HFA ; 6I29 ; 6I3S ; 6IM9 ; 6KZU ; 6Q96 ; 6Q9H ; 6Q9L ; 6Q9O ; 6SQO ; 6T2D ; 6T2E ; 6T2F ; 6Y4Q ; 6YR6 ; 7AD0 ; 7AI0 ; 7AI1 ; 7AYE ; 7BIR ; 7BIT ; 7BIV ; 7BJ0 ; 7BJ6 ; 7BMG ; 7KJM ; 7NA1 ; 7NA2 ; 7NA3 ; 7NA4 ; 7NUS ; 7QDQ ; 8AEU ; 8BGU ; 8EI9 ; 8EIA ; 8EIB ; 8EIC ; 8F0Z ; 8F10 ; 8F12 ; 8F13
• EC Number: 2.3.2.27
• Pfam ID: PF02201 ; PF13920 ; PF00641
• Sequence:
  MCNTNMSVPTDGAVTTSQIPASEQETLVRPKPLLLKLLKSVGAQKDTYTMKEVLFYLGQY
  IMTKRLYDEKQQHIVYCSNDLLGDLFGVPSFSVKEHRKIYTMIYRNLVVVNQQESSDSGT
  SVSENRCHLEGGSDQKDLVQELQEEKPSSSHLVSRPSTSSRRRAISETEENSDELSGERQ
  RKRHKSDSISLSFDESLALCVIREICCERSSSSESTGTPSNPDLDAGVSEHSGDWLDQDS
  VSDQFSVEFEVESLDSEDYSLSEEGQELSDEDDEVYQVTVYQAGESDTDSFEEDPEISLA
  DYWKCTSCNEMNPPLPSHCNRCWALRENWLPEDKGKDKGEISEKAKLENSTQAEEGFDVP
  DCKKTIVNDSRESCVEENDDKITQASQSQESEDYSQPSTSSSIIYSSQEDVKEFEREETQ
  DKEESVESSLPLNAIEPCVICQGRPKNGCIVHGKTGHLMACFTCAKKLKKRNKPCPVCRQ
  PIQMIVLTYFP
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. 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 a 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. Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis.
• Tissue Specificity: Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Platinum drug resistance (hsa01524)
  FoxO sig.ling pathway (hsa04068)
  Cell cycle (hsa04110)
  p53 sig.ling pathway (hsa04115)
  Ubiquitin mediated proteolysis (hsa04120)
  Endocytosis (hsa04144)
  PI3K-Akt sig.ling pathway (hsa04151)
  Cellular senescence (hsa04218)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Thyroid hormone sig.ling pathway (hsa04919)
  Shigellosis (hsa05131)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Epstein-Barr virus infection (hsa05169)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  MicroR.s 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)
  SUMOylation of transcription factors (R-HSA-3232118)
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  Trafficking of AMPA receptors (R-HSA-399719)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  Ub-specific processing proteases (R-HSA-5689880)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  Regulation of TP53 Degradation (R-HSA-6804757)
  Regulation of TP53 Activity through Methylation (R-HSA-6804760)
  Stabilization of p53 (R-HSA-69541)
  Regulation of RUNX3 expression and activity (R-HSA-8941858)
  NPAS4 regulates expression of target genes (R-HSA-9768919)
  AKT phosphorylates targets in the cytosol (R-HSA-198323)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lessel-kubisch syndrome	DISPUB7O	Limited	Unknown	[1]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	E3 ubiquitin-protein ligase Mdm2 (MDM2) decreases the response to substance of Paclitaxel.	[81]
Mitoxantrone	DMM39BF	Approved	E3 ubiquitin-protein ligase Mdm2 (MDM2) decreases the response to substance of Mitoxantrone.	[82]
Amsacrine	DMZKYIV	Approved	E3 ubiquitin-protein ligase Mdm2 (MDM2) decreases the response to substance of Amsacrine.	[82]
Ellipticine	DMHPYSM	Investigative	E3 ubiquitin-protein ligase Mdm2 (MDM2) decreases the response to substance of Ellipticine.	[82]
10-hydroxycamptothecin	DM9WLN4	Investigative	E3 ubiquitin-protein ligase Mdm2 (MDM2) affects the response to substance of 10-hydroxycamptothecin.	[81]

78 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[15]
Menadione	DMSJDTY	Approved	Menadione decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[18]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[19]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[20]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[21]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[23]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[24]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[25]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[26]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[27]
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[28]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[7]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[29]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[24]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[31]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[32]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[24]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[33]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[34]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[34]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[35]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[36]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[24]
Docetaxel	DMDI269	Approved	Docetaxel increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[37]
Cantharidin	DMBP5N3	Approved	Cantharidin decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[38]
Chlorambucil	DMRKE63	Approved	Chlorambucil increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[39]
Nicotinamide	DMUPE07	Approved	Nicotinamide increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[40]
Amifostine	DM5FL14	Approved	Amifostine decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[41]
Flucytosine	DM13VTW	Approved	Flucytosine increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[42]
Ganciclovir	DM1MBYQ	Approved	Ganciclovir increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[42]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[40]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[36]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[43]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[44]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[45]
Triptolide	DMCMDVR	Phase 3	Triptolide decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[46]
Selinexor	DMBD4K3	Phase 3	Selinexor increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[47]
Thymoquinone	DMVDTR2	Phase 2/3	Thymoquinone decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[48]
Flavopiridol	DMKSUOI	Phase 2	Flavopiridol decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[50]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[52]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[53]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[54]
LY294002	DMY1AFS	Phase 1	LY294002 increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[56]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[57]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[59]
PJ34	DMXO6YH	Preclinical	PJ34 increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[60]
IC261	DMXB95R	Preclinical	IC261 affects the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[61]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[62]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[63]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[64]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[65]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[66]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[67]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[68]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[69]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[70]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[71]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[72]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[73]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[74]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[75]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[76]
PD98059	DMZC90M	Investigative	PD98059 decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[77]
Purvalanol A	DMNQ7TM	Investigative	Purvalanol A decreases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[79]
ODQ	DMSAJO8	Investigative	ODQ increases the expression of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[80]

6 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the phosphorylation of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[16]
Simvastatin	DM30SGU	Approved	Simvastatin increases the phosphorylation of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[30]
PX-866	DMYISJK	Phase 2	PX-866 decreases the phosphorylation of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[51]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[55]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[58]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	Bortezomib increases the cleavage of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[22]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin increases the degradation of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[49]
PALMATINE	DMJCOKV	Investigative	PALMATINE affects the binding of E3 ubiquitin-protein ligase Mdm2 (MDM2).	[78]

References

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