Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR8ACBF)

• DOT Name: Serine protease HTRA1 (HTRA1)
• Synonyms: EC 3.4.21.-; High-temperature requirement A serine peptidase 1; L56; Serine protease 11
• Gene Name: HTRA1
• Related Disease:
  CARASIL syndrome
  Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2
  Obsolete genetic cerebral small vessel disease
  HTRA1-related autosomal dominant cerebral small vessel disease
• UniProt ID: HTRA1_HUMAN
• PDB ID: 2JOA; 2YTW; 3NUM; 3NWU; 3NZI; 3TJN; 3TJO; 3TJQ; 6Z0E; 6Z0X; 6Z0Y; 7SJN; 7SJO; 7SJP
• EC Number: 3.4.21.-
• Pfam ID: PF00219 ; PF07648 ; PF17820 ; PF13365
• Sequence:
  MQIPRAALLPLLLLLLAAPASAQLSRAGRSAPLAAGCPDRCEPARCPPQPEHCEGGRARD
  ACGCCEVCGAPEGAACGLQEGPCGEGLQCVVPFGVPASATVRRRAQAGLCVCASSEPVCG
  SDANTYANLCQLRAASRRSERLHRPPVIVLQRGACGQGQEDPNSLRHKYNFIADVVEKIA
  PAVVHIELFRKLPFSKREVPVASGSGFIVSEDGLIVTNAHVVTNKHRVKVELKNGATYEA
  KIKDVDEKADIALIKIDHQGKLPVLLLGRSSELRPGEFVVAIGSPFSLQNTVTTGIVSTT
  QRGGKELGLRNSDMDYIQTDAIINYGNSGGPLVNLDGEVIGINTLKVTAGISFAIPSDKI
  KKFLTESHDRQAKGKAITKKKYIGIRMMSLTSSKAKELKDRHRDFPDVISGAYIIEVIPD
  TPAEAGGLKENDVIISINGQSVVSANDVSDVIKRESTLNMVVRRGNEDIMITVIPEEIDP
• Function: Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets.
• Tissue Specificity: Widely expressed, with strongest expression in placenta (at protein level). Secreted by synovial fibroblasts. Up-regulated in osteoarthritis and rheumatoid arthritis synovial fluids and cartilage as compared with non-arthritic (at protein level).
• Reactome Pathway: Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CARASIL syndrome	DIS7KGGR	Strong	Autosomal recessive	[1]
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2	DISL7FVN	Strong	Autosomal dominant	[1]
Obsolete genetic cerebral small vessel disease	DISZMFSU	Strong	Autosomal dominant	[2]
HTRA1-related autosomal dominant cerebral small vessel disease	DISJT0KF	Supportive	Autosomal dominant	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Serine protease HTRA1 (HTRA1) affects the response to substance of Doxorubicin.	[26]
Deoxycholic acid	DM3GYAL	Approved	Serine protease HTRA1 (HTRA1) affects the response to substance of Deoxycholic acid.	[27]

25 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 HTRA1 (HTRA1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine protease HTRA1 (HTRA1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine protease HTRA1 (HTRA1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine protease HTRA1 (HTRA1).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Serine protease HTRA1 (HTRA1).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Serine protease HTRA1 (HTRA1).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Serine protease HTRA1 (HTRA1).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Serine protease HTRA1 (HTRA1).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Serine protease HTRA1 (HTRA1).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine protease HTRA1 (HTRA1).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Serine protease HTRA1 (HTRA1).	[13]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Serine protease HTRA1 (HTRA1).	[14]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Serine protease HTRA1 (HTRA1).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Serine protease HTRA1 (HTRA1).	[16]
Gefitinib	DM15F0X	Approved	Gefitinib increases the expression of Serine protease HTRA1 (HTRA1).	[8]
Tirbanibulin	DMJNV4O	Approved	Tirbanibulin increases the expression of Serine protease HTRA1 (HTRA1).	[8]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Serine protease HTRA1 (HTRA1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Serine protease HTRA1 (HTRA1).	[18]
BMS-582949	DMGYXFP	Phase 2	BMS-582949 decreases the expression of Serine protease HTRA1 (HTRA1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Serine protease HTRA1 (HTRA1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine protease HTRA1 (HTRA1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Serine protease HTRA1 (HTRA1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Serine protease HTRA1 (HTRA1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Serine protease HTRA1 (HTRA1).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Serine protease HTRA1 (HTRA1).	[25]

1 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 decreases the methylation of Serine protease HTRA1 (HTRA1).	[19]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. Brain. 2015 Aug;138(Pt 8):2347-58. doi: 10.1093/brain/awv155. Epub 2015 Jun 10.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [14] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [17] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [18] 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.
• [19] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [20] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [21] 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.
• [22] Low dose of bisphenol a modulates ovarian cancer gene expression profile and promotes epithelial to mesenchymal transition via canonical Wnt pathway. Toxicol Sci. 2018 Aug 1;164(2):527-538.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [25] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [26] Gene expression profile associated with response to doxorubicin-based therapy in breast cancer. Clin Cancer Res. 2005 Oct 15;11(20):7434-43. doi: 10.1158/1078-0432.CCR-04-0548.
• [27] Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. Carcinogenesis. 2002 Dec;23(12):2063-80. doi: 10.1093/carcin/23.12.2063.