Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7QNA61)

• DOT Name: Serine protease hepsin (HPN)
• Synonyms: EC 3.4.21.106; Transmembrane protease serine 1
• Gene Name: HPN
• UniProt ID: HEPS_HUMAN
• PDB ID: 1O5E; 1O5F; 1P57; 1Z8G; 3T2N; 5CE1
• EC Number: 3.4.21.106
• Pfam ID: PF09272 ; PF00089
• Sequence:
  MAQKEGGRTVPCCSRPKVAALTAGTLLLLTAIGAASWAIVAVLLRSDQEPLYPVQVSSAD
  ARLMVFDKTEGTWRLLCSSRSNARVAGLSCEEMGFLRALTHSELDVRTAGANGTSGFFCV
  DEGRLPHTQRLLEVISVCDCPRGRFLAAICQDCGRRKLPVDRIVGGRDTSLGRWPWQVSL
  RYDGAHLCGGSLLSGDWVLTAAHCFPERNRVLSRWRVFAGAVAQASPHGLQLGVQAVVYH
  GGYLPFRDPNSEENSNDIALVHLSSPLPLTEYIQPVCLPAAGQALVDGKICTVTGWGNTQ
  YYGQQAGVLQEARVPIISNDVCNGADFYGNQIKPKMFCAGYPEGGIDACQGDSGGPFVCE
  DSISRTPRWRLCGIVSWGTGCALAQKPGVYTKVSDFREWIFQAIKTHSEASGMVTQL
• Function: Serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL. Plays a role in cell growth and maintenance of cell morphology. Plays a role in the proteolytic processing of ACE2. Mediates the proteolytic cleavage of urinary UMOD that is required for UMOD polymerization.
• Tissue Specificity: Detected in liver and kidney.
• KEGG Pathway: Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Signaling by MST1 (R-HSA-8852405)
  MET Receptor Activation (R-HSA-6806942)

Molecular Interaction Atlas (MIA) of This DOT

27 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 Serine protease hepsin (HPN).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine protease hepsin (HPN).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine protease hepsin (HPN).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine protease hepsin (HPN).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Serine protease hepsin (HPN).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Serine protease hepsin (HPN).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Serine protease hepsin (HPN).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine protease hepsin (HPN).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Serine protease hepsin (HPN).	[9]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Serine protease hepsin (HPN).	[10]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Serine protease hepsin (HPN).	[10]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Serine protease hepsin (HPN).	[10]
Thioridazine	DM35M8J	Approved	Thioridazine increases the expression of Serine protease hepsin (HPN).	[10]
Imipramine	DM2NUH3	Approved	Imipramine increases the expression of Serine protease hepsin (HPN).	[10]
Clomipramine	DMINRKW	Approved	Clomipramine increases the expression of Serine protease hepsin (HPN).	[10]
Erythromycin	DM4K7GQ	Approved	Erythromycin increases the expression of Serine protease hepsin (HPN).	[3]
Loratadine	DMF3AN7	Approved	Loratadine increases the expression of Serine protease hepsin (HPN).	[10]
Pentamidine	DMHZJCG	Approved	Pentamidine increases the expression of Serine protease hepsin (HPN).	[10]
Flecainide	DMSQDLE	Approved	Flecainide increases the expression of Serine protease hepsin (HPN).	[3]
Perhexiline	DMINO7Z	Approved	Perhexiline increases the expression of Serine protease hepsin (HPN).	[10]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Serine protease hepsin (HPN).	[10]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Serine protease hepsin (HPN).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine protease hepsin (HPN).	[2]
Chlorcyclizine	DM3L52Q	Phase 1	Chlorcyclizine increases the expression of Serine protease hepsin (HPN).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine protease hepsin (HPN).	[11]
ZIMELIDINE	DMNI3U2	Withdrawn from market	ZIMELIDINE increases the expression of Serine protease hepsin (HPN).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Serine protease hepsin (HPN).	[12]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells. Toxicol Sci. 2007 Mar;96(1):101-14.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [10] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.