Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSFOX2H)

• DOT Name: Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1)
• Gene Name: KAZALD1
• Related Disease:
  Astrocytoma
  Glioblastoma multiforme
  Glioma
  Malignant glioma
  Malignant pleural mesothelioma
  Peritoneal mesothelioma
• UniProt ID: KAZD1_HUMAN
• Pfam ID: PF07679 ; PF00219 ; PF07648
• Sequence:
  MLPPPRPAAALALPVLLLLLVVLTPPPTGARPSPGPDYLRRGWMRLLAEGEGCAPCRPEE
  CAAPRGCLAGRVRDACGCCWECANLEGQLCDLDPSAHFYGHCGEQLECRLDTGGDLSRGE
  VPEPLCACRSQSPLCGSDGHTYSQICRLQEAARARPDANLTVAHPGPCESGPQIVSHPYD
  TWNVTGQDVIFGCEVFAYPMASIEWRKDGLDIQLPGDDPHISVQFRGGPQRFEVTGWLQI
  QAVRPSDEGTYRCLGRNALGQVEAPASLTVLTPDQLNSTGIPQLRSLNLVPEEEAESEEN
  DDYY
• Function: Involved in the proliferation of osteoblasts during bone formation and bone regeneration. Promotes matrix assembly.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Astrocytoma	DISL3V18	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Malignant glioma	DISFXKOV	Strong	Biomarker	[1]
Malignant pleural mesothelioma	DIST2R60	Limited	Biomarker	[2]
Peritoneal mesothelioma	DISW7W4V	Limited	Genetic Variation	[2]

3 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 Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[11]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Kazal-type serine protease inhibitor domain-containing protein 1 (KAZALD1).	[17]

References

• [1] Epigenetic silencing of KAZALD1 confers a better prognosis and is associated with malignant transformation/progression in glioma.Oncol Rep. 2013 Nov;30(5):2089-96. doi: 10.3892/or.2013.2706. Epub 2013 Aug 29.
• [2] Characterization of DNA hypermethylation in two cases of peritoneal mesothelioma.Tumour Biol. 2012 Dec;33(6):2031-40. doi: 10.1007/s13277-012-0462-8. Epub 2012 Jul 27.
• [3] 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.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] 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.
• [17] 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.