Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWICA51)

• DOT Name: 26S proteasome non-ATPase regulatory subunit 12 (PSMD12)
• Synonyms: 26S proteasome regulatory subunit RPN5; 26S proteasome regulatory subunit p55
• Gene Name: PSMD12
• Related Disease:
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Stankiewicz-Isidor syndrome
  Acute lymphocytic leukaemia
  Adult glioblastoma
  Adult respiratory distress syndrome
  Ankylosing spondylitis
  Bladder cancer
  Bone osteosarcoma
  Classic Hodgkin lymphoma
  Glioblastoma multiforme
  Intellectual disability
  Isolated congenital microcephaly
  Mixed connective tissue disease
  Monocytic leukemia
  Multiple sclerosis
  Neurodevelopmental disorder
  Osteoarthritis
  Osteosarcoma
  Rheumatoid arthritis
  Sarcoidosis
  Subacute cutaneous lupus erythematosus
  Systemic lupus erythematosus
  T-cell leukaemia
  Urinary bladder cancer
  Urinary bladder neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Type-1 diabetes
  Syndromic intellectual disability
  Pneumonia
  Acute myelogenous leukaemia
  Arthritis
  Autism spectrum disorder
  Contact dermatitis
  Neoplasm
  Pneumocystis pneumonia
• UniProt ID: PSD12_HUMAN
• PDB ID: 5GJQ ; 5GJR ; 5L4K ; 5LN3 ; 5M32 ; 5T0C ; 5T0G ; 5T0H ; 5T0I ; 5T0J ; 5VFP ; 5VFQ ; 5VFR ; 5VFS ; 5VFT ; 5VFU ; 5VGZ ; 5VHF ; 5VHH ; 5VHI ; 5VHS ; 6MSB ; 6MSD ; 6MSE ; 6MSG ; 6MSH ; 6MSJ ; 6MSK ; 6WJD ; 6WJN ; 7QXN ; 7QXP ; 7QXU ; 7QXW ; 7QXX ; 7QY7 ; 7QYA ; 7QYB ; 7W37 ; 7W38 ; 7W39 ; 7W3A ; 7W3B ; 7W3C ; 7W3F ; 7W3G ; 7W3H ; 7W3I ; 7W3J ; 7W3K ; 7W3M ; 8CVT
• Pfam ID: PF01399 ; PF18098
• Sequence:
  MADGGSERADGRIVKMEVDYSATVDQRLPECAKLAKEGRLQEVIETLLSLEKQTRTASDM
  VSTSRILVAVVKMCYEAKEWDLLNENIMLLSKRRSQLKQAVAKMVQQCCTYVEEITDLPI
  KLRLIDTLRMVTEGKIYVEIERARLTKTLATIKEQNGDVKEAASILQELQVETYGSMEKK
  ERVEFILEQMRLCLAVKDYIRTQIISKKINTKFFQEENTEKLKLKYYNLMIQLDQHEGSY
  LSICKHYRAIYDTPCIQAESEKWQQALKSVVLYVILAPFDNEQSDLVHRISGDKKLEEIP
  KYKDLLKLFTTMELMRWSTLVEDYGMELRKGSLESPATDVFGSTEEGEKRWKDLKNRVVE
  HNIRIMAKYYTRITMKRMAQLLDLSVDESEAFLSNLVVNKTIFAKVDRLAGIINFQRPKD
  PNNLLNDWSQKLNSLMSLVNKTTHLIAKEEMIHNLQ
• Function: Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.
• KEGG Pathway:
  Proteasome (hsa03050)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Epstein-Barr virus infection (hsa05169)
• Reactome Pathway:
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)
  ER-Phagosome pathway (R-HSA-1236974)
  Cross-presentation of soluble exogenous antigens (endosomes) (R-HSA-1236978)
  Autodegradation of Cdh1 by Cdh1 (R-HSA-174084)
  SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113)
  APC/C (R-HSA-174154)
  APC/C (R-HSA-174178)
  Cdc20 (R-HSA-174184)
  Vpu mediated degradation of CD4 (R-HSA-180534)
  Vif-mediated degradation of APOBEC3G (R-HSA-180585)
  SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Downstream TCR signaling (R-HSA-202424)
  Regulation of activated PAK-2p34 by proteasome mediated degradation (R-HSA-211733)
  Separation of Sister Chromatids (R-HSA-2467813)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425)
  Regulation of ornithine decarboxylase (ODC) (R-HSA-350562)
  ABC-family proteins mediated transport (R-HSA-382556)
  AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  Degradation of AXIN (R-HSA-4641257)
  Degradation of DVL (R-HSA-4641258)
  Hedgehog ligand biogenesis (R-HSA-5358346)
  Hh mutants are degraded by ERAD (R-HSA-5362768)
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)
  Degradation of GLI2 by the proteasome (R-HSA-5610783)
  GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785)
  Hedgehog 'on' state (R-HSA-5632684)
  Regulation of RAS by GAPs (R-HSA-5658442)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  UCH proteinases (R-HSA-5689603)
  Ub-specific processing proteases (R-HSA-5689880)
  Neutrophil degranulation (R-HSA-6798695)
  Assembly of the pre-replicative complex (R-HSA-68867)
  Orc1 removal from chromatin (R-HSA-68949)
  CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017)
  G2/M Checkpoints (R-HSA-69481)
  Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-HSA-69601)
  Ubiquitin-dependent degradation of Cyclin D (R-HSA-75815)
  The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276)
  FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  Regulation of RUNX3 expression and activity (R-HSA-8941858)
  Regulation of PTEN stability and activity (R-HSA-8948751)
  Neddylation (R-HSA-8951664)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Interleukin-1 signaling (R-HSA-9020702)
  Negative regulation of NOTCH4 signaling (R-HSA-9604323)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  GSK3B and BTRC (R-HSA-9762114)
  Somitogenesis (R-HSA-9824272)
  Antigen processing (R-HSA-983168)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Definitive	Biomarker	[1]
Stankiewicz-Isidor syndrome	DIS5V84P	Definitive	Autosomal dominant	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[4]
Adult respiratory distress syndrome	DISIJV47	Strong	Biomarker	[5]
Ankylosing spondylitis	DISRC6IR	Strong	Genetic Variation	[6]
Bladder cancer	DISUHNM0	Strong	Biomarker	[7]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[8]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[9]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[10]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[11]
Mixed connective tissue disease	DISXX0H8	Strong	Biomarker	[12]
Monocytic leukemia	DIS8M755	Strong	Biomarker	[13]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[6]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[10]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[14]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[15]
Sarcoidosis	DISE5B8Z	Strong	Biomarker	[16]
Subacute cutaneous lupus erythematosus	DIS6XDK0	Strong	Biomarker	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[12]
T-cell leukaemia	DISJ6YIF	Strong	Altered Expression	[17]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Altered Expression	[18]
Liver cancer	DISDE4BI	moderate	Altered Expression	[18]
Type-1 diabetes	DIS7HLUB	moderate	Altered Expression	[19]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[11]
Pneumonia	DIS8EF3M	Disputed	Biomarker	[20]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[21]
Arthritis	DIST1YEL	Limited	Genetic Variation	[22]
Autism spectrum disorder	DISXK8NV	Limited	Genetic Variation	[10]
Contact dermatitis	DISQ3AU0	Limited	Biomarker	[23]
Neoplasm	DISZKGEW	Limited	Biomarker	[24]
Pneumocystis pneumonia	DISFSOM3	Limited	Biomarker	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[26]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[28]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[30]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[31]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[32]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[33]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[34]
Menadione	DMSJDTY	Approved	Menadione increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[33]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[35]
Aspirin	DM672AH	Approved	Aspirin increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[36]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[37]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[39]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[42]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[43]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[44]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[45]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[46]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[47]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[38]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of 26S proteasome non-ATPase regulatory subunit 12 (PSMD12).	[40]

References

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• [34] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
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