Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTXU3EQ)

• DTT Name: Herpesvirus ubiquitin-specific protease (HAUSP)
• Synonyms: Ubiquitin-specific-processing protease 7; Ubiquitin thioesterase 7; Ubiquitin carboxyl-terminal hydrolase 7; Herpesvirus-associated ubiquitin-specific protease; Deubiquitinating enzyme 7
• Gene Name: USP7
• DTT Type: Preclinical target; [1]
• BioChemical Class: Peptidase
• UniProt ID: UBP7_HUMAN
• TTD ID: T42658
• EC Number: EC 3.4.19.12
• Sequence:
  MNHQQQQQQQKAGEQQLSEPEDMEMEAGDTDDPPRITQNPVINGNVALSDGHNTAEEDME
  DDTSWRSEATFQFTVERFSRLSESVLSPPCFVRNLPWKIMVMPRFYPDRPHQKSVGFFLQ
  CNAESDSTSWSCHAQAVLKIINYRDDEKSFSRRISHLFFHKENDWGFSNFMAWSEVTDPE
  KGFIDDDKVTFEVFVQADAPHGVAWDSKKHTGYVGLKNQGATCYMNSLLQTLFFTNQLRK
  AVYMMPTEGDDSSKSVPLALQRVFYELQHSDKPVGTKKLTKSFGWETLDSFMQHDVQELC
  RVLLDNVENKMKGTCVEGTIPKLFRGKMVSYIQCKEVDYRSDRREDYYDIQLSIKGKKNI
  FESFVDYVAVEQLDGDNKYDAGEHGLQEAEKGVKFLTLPPVLHLQLMRFMYDPQTDQNIK
  INDRFEFPEQLPLDEFLQKTDPKDPANYILHAVLVHSGDNHGGHYVVYLNPKGDGKWCKF
  DDDVVSRCTKEEAIEHNYGGHDDDLSVRHCTNAYMLVYIRESKLSEVLQAVTDHDIPQQL
  VERLQEEKRIEAQKRKERQEAHLYMQVQIVAEDQFCGHQGNDMYDEEKVKYTVFKVLKNS
  SLAEFVQSLSQTMGFPQDQIRLWPMQARSNGTKRPAMLDNEADGNKTMIELSDNENPWTI
  FLETVDPELAASGATLPKFDKDHDVMLFLKMYDPKTRSLNYCGHIYTPISCKIRDLLPVM
  CDRAGFIQDTSLILYEEVKPNLTERIQDYDVSLDKALDELMDGDIIVFQKDDPENDNSEL
  PTAKEYFRDLYHRVDVIFCDKTIPNDPGFVVTLSNRMNYFQVAKTVAQRLNTDPMLLQFF
  KSQGYRDGPGNPLRHNYEGTLRDLLQFFKPRQPKKLYYQQLKMKITDFENRRSFKCIWLN
  SQFREEEITLYPDKHGCVRDLLEECKKAVELGEKASGKLRLLEIVSYKIIGVHQEDELLE
  CLSPATSRTFRIEEIPLDQVDIDKENEMLVTVAHFHKEVFGTFGIPFLLRIHQGEHFREV
  MKRIQSLLDIQEKEFEKFKFAIVMMGRHQYINEDEYEVNLKDFEPQPGNMSHPRPWLGLD
  HFNKAPKRSRYTYLEKAIKIHN
• Function: Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation. Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis. Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis. Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity. In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML. Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation. Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6. Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1. Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions. Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex. Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo. Exhibits a preference towards 'Lys-48'-linked ubiquitin chains. Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function. Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins. Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells. Hydrolase that deubiquitinates target proteins such as FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX.
• KEGG Pathway:
  FoxO signaling pathway (hsa04068)
  Epstein-Barr virus infection (hsa05169)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Regulation of TP53 Degradation (R-HSA-6804757)
  Synthesis of active ubiquitin (R-HSA-8866652)
  Regulation of PTEN localization (R-HSA-8948747)
  Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DTT

2 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID26077642-Compound-Vif1	DMS9KCF	N. A.	N. A.	Patented	[1]
PMID26077642-Compound-Vif2	DMYXIS7	N. A.	N. A.	Patented	[1]

5 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ADC-01	DM19R28	Solid tumour/cancer	2A00-2F9Z	Preclinical	[2]
ADC-03	DM21I35	Solid tumour/cancer	2A00-2F9Z	Preclinical	[2]
HBX19818	DM6GSI1	Solid tumour/cancer	2A00-2F9Z	Preclinical	[3]
P22077	DMD8JIC	Inflammation	1A00-CA43.1	Preclinical	[4]
P5091	DMGIR3F	Solid tumour/cancer	2A00-2F9Z	Preclinical	[5]

References

• [1] Deubiquitinases (DUBs) and DUB inhibitors: a patent review.Expert Opin Ther Pat. 2015;25(10):1191-1208.
• [2] Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics. Cancers (Basel). 2020 Jun 15;12(6):1579.
• [3] Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells. Mol Cancer Ther. 2009 Aug;8(8):2286-95.
• [4] P22077 inhibits LPS-induced inflammatory response by promoting K48-linked ubiquitination and degradation of TRAF6. Aging (Albany NY). 2020 Jun 9;12(11):10969-10982.
• [5] USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth. Biochem Pharmacol. 2017 May 1;131:29-39.