Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXJ0H4X)

• DOT Name: Serine protease HTRA3 (HTRA3)
• Synonyms: EC 3.4.21.-; High-temperature requirement factor A3; Pregnancy-related serine protease
• Gene Name: HTRA3
• Related Disease:
  Endometrial cancer
  Endometrial carcinoma
  Advanced cancer
  Clear cell renal carcinoma
  Cockayne syndrome
  Colorectal carcinoma
  Endometrium neoplasm
  Epithelial ovarian cancer
  Lung neoplasm
  Metastatic malignant neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Oral cancer
  Ovarian cancer
  Ovarian neoplasm
  Precancerous condition
  Renal cell carcinoma
  Urinary bladder neoplasm
  Hypertension, pregnancy-induced
  Lung cancer
  Lung carcinoma
  Pneumonia
  Benign neoplasm
  Cutaneous mastocytosis
  Granulosa cell tumor
  Thyroid gland follicular carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
• UniProt ID: HTRA3_HUMAN
• PDB ID: 2P3W; 4RI0
• EC Number: 3.4.21.-
• Pfam ID: PF00219 ; PF07648 ; PF17820 ; PF13365
• Sequence:
  MQARALLLAALAALALAREPPAAPCPARCDVSRCPSPRCPGGYVPDLCNCCLVCAASEGE
  PCGGPLDSPCGESLECVRGLCRCRWSHAVCGTDGHTYANVCALQAASRRALQLSGTPVRQ
  LQKGACPLGLHQLSSPRYKFNFIADVVEKIAPAVVHIELFLRHPLFGRNVPLSSGSGFIM
  SEAGLIITNAHVVSSNSAAPGRQQLKVQLQNGDSYEATIKDIDKKSDIATIKIHPKKKLP
  VLLLGHSADLRPGEFVVAIGSPFALQNTVTTGIVSTAQREGRELGLRDSDMDYIQTDAII
  NYGNSGGPLVNLDGEVIGINTLKVTAGISFAIPSDRITRFLTEFQDKQIKDWKKRFIGIR
  MRTITPSLVDELKASNPDFPEVSSGIYVQEVAPNSPSQRGGIQDGDIIVKVNGRPLVDSS
  ELQEAVLTESPLLLEVRRGNDDLLFSIAPEVVM
• Function: Serine protease that cleaves beta-casein/CSN2 as well as several extracellular matrix (ECM) proteoglycans such as decorin/DCN, biglycan/BGN and fibronectin/FN1. Inhibits signaling mediated by TGF-beta family proteins possibly indirectly by degradation of these ECM proteoglycans. May act as a tumor suppressor. Negatively regulates, in vitro, trophoblast invasion during placental development and may be involved in the development of the placenta in vivo. May also have a role in ovarian development, granulosa cell differentiation and luteinization.
• Tissue Specificity: Widely expressed, with highest levels in both adult and fetal heart, ovary, uterus placenta, and bladder. In the endometrium, expressed in epithelial glands and the stroma. Also present in leukocytes. Isoform 1 is predominant in heart and skeletal muscle, whereas isoform 2 is predominant in placenta and kidney.

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Endometrial cancer	DISW0LMR	Definitive	Biomarker	[1]
Endometrial carcinoma	DISXR5CY	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Cockayne syndrome	DISW6GL2	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Endometrium neoplasm	DIS6OS2L	Strong	Altered Expression	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[7]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Oral cancer	DISLD42D	Strong	Biomarker	[9]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[7]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[7]
Precancerous condition	DISV06FL	Strong	Altered Expression	[1]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[10]
Hypertension, pregnancy-induced	DISHNU25	moderate	Altered Expression	[11]
Lung cancer	DISCM4YA	moderate	Biomarker	[8]
Lung carcinoma	DISTR26C	moderate	Biomarker	[8]
Pneumonia	DIS8EF3M	Disputed	Altered Expression	[12]
Benign neoplasm	DISDUXAD	Limited	Altered Expression	[13]
Cutaneous mastocytosis	DISLBZEF	Limited	Altered Expression	[14]
Granulosa cell tumor	DISKWVAB	Limited	Altered Expression	[7]
Thyroid gland follicular carcinoma	DISFK2QT	Limited	Altered Expression	[13]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[13]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Serine protease HTRA3 (HTRA3).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Serine protease HTRA3 (HTRA3).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine protease HTRA3 (HTRA3).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine protease HTRA3 (HTRA3).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serine protease HTRA3 (HTRA3).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine protease HTRA3 (HTRA3).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine protease HTRA3 (HTRA3).	[21]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of Serine protease HTRA3 (HTRA3).	[22]

References

• [1] Hypoxia is involved in the reduction of HtrA3 in patients with endometrial hyperplasia and cancer.Biochem Biophys Res Commun. 2018 Sep 18;503(4):2918-2923. doi: 10.1016/j.bbrc.2018.08.070. Epub 2018 Aug 20.
• [2] Identification of a distal allosteric ligand binding pocket in HtrA3.Biochem Biophys Res Commun. 2019 Sep 3;516(4):1130-1136. doi: 10.1016/j.bbrc.2019.07.005. Epub 2019 Jul 5.
• [3] HtrA3 is regulated by 15-deoxy-Delta12,14-prostaglandin J2 independently of PPARgamma in clear cell renal cell carcinomas.Biochem Biophys Res Commun. 2010 Apr 9;394(3):453-8. doi: 10.1016/j.bbrc.2009.11.163. Epub 2009 Nov 29.
• [4] CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence.Nat Commun. 2019 Dec 6;10(1):5576. doi: 10.1038/s41467-019-13314-y.
• [5] HtrA3 stromal expression is correlated with tumor budding in stage II colorectal cancer.Exp Mol Pathol. 2017 Aug;103(1):94-100. doi: 10.1016/j.yexmp.2017.07.002. Epub 2017 Jul 15.
• [6] Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer.Gynecol Oncol. 2006 Oct;103(1):253-60. doi: 10.1016/j.ygyno.2006.03.006. Epub 2006 May 2.
• [7] High-temperature requirement factor A3 (Htra3): a novel serine protease and its potential role in ovarian function and ovarian cancers.Mol Cell Endocrinol. 2010 Oct 7;327(1-2):13-8. doi: 10.1016/j.mce.2010.06.001. Epub 2010 Jun 9.
• [8] Antagonism between HTRA3 and TGF1 Contributes to Metastasis in Non-Small Cell Lung Cancer.Cancer Res. 2019 Jun 1;79(11):2853-2864. doi: 10.1158/0008-5472.CAN-18-2507. Epub 2019 Apr 2.
• [9] The high-temperature requirement factor A3 (HtrA3) is associated with acquisition of the invasive phenotype in oral squamous cell carcinoma cells.Oral Oncol. 2015 Jan;51(1):84-9. doi: 10.1016/j.oraloncology.2014.10.001. Epub 2014 Oct 24.
• [10] OASIS/CREB3L1 is epigenetically silenced in human bladder cancer facilitating tumor cell spreading and migration in vitro.Epigenetics. 2014 Dec;9(12):1626-40. doi: 10.4161/15592294.2014.988052.
• [11] Low Serum Levels of HtrA3 at 15 Weeks of Gestation Are Associated with Late-Onset Preeclampsia Development and Small for Gestational Age Birth.Fetal Diagn Ther. 2019;46(6):392-401. doi: 10.1159/000497144. Epub 2019 Apr 23.
• [12] Design, Synthesis, and Biological Evaluation of Novel 7-[(3 aS,7 aS)-3 a-Aminohexahydropyrano[3,4- c]pyrrol-2(3 H)-yl]-8-methoxyquinolines with Potent Antibacterial Activity against Respiratory Pathogens.J Med Chem. 2018 Aug 23;61(16):7234-7244. doi: 10.1021/acs.jmedchem.8b00644. Epub 2018 Aug 8.
• [13] Changes in expression of human serine protease HtrA1, HtrA2 and HtrA3 genes in benign and malignant thyroid tumors.Oncol Rep. 2012 Nov;28(5):1838-44. doi: 10.3892/or.2012.1988. Epub 2012 Aug 23.
• [14] Immune response against HtrA proteases in children with cutaneous mastocytosis.Acta Biochim Pol. 2018;65(3):471-478. doi: 10.18388/abp.2018_2623. Epub 2018 Aug 27.
• [15] 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.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [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] 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.
• [21] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [22] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.