Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8PQUVB)

• DOT Name: Secreted frizzled-related protein 4 (SFRP4)
• Synonyms: sFRP-4; Frizzled protein, human endometrium; FrpHE
• Gene Name: SFRP4
• Related Disease: Pyle disease
• UniProt ID: SFRP4_HUMAN
• Pfam ID: PF01392 ; PF01759
• Sequence:
  MFLSILVALCLWLHLALGVRGAPCEAVRIPMCRHMPWNITRMPNHLHHSTQENAILAIEQ
  YEELVDVNCSAVLRFFLCAMYAPICTLEFLHDPIKPCKSVCQRARDDCEPLMKMYNHSWP
  ESLACDELPVYDRGVCISPEAIVTDLPEDVKWIDITPDMMVQERPLDVDCKRLSPDRCKC
  KKVKPTLATYLSKNYSYVIHAKIKAVQRSGCNEVTTVVDVKEIFKSSSPIPRTQVPLITN
  SSCQCPHILPHQDVLIMCYEWRSRMMLLENCLVEKWRDQLSKRSIQWEERLQEQRRTVQD
  KKKTAGRTSRSNPPKPKGKPPAPKPASPKKNIKTRSAQKRTNPKRV
• Function: Soluble frizzled-related proteins (sFRPS) function as modulators of Wnt signaling through direct interaction with Wnts. They have a role in regulating cell growth and differentiation in specific cell types. SFRP4 plays a role in bone morphogenesis. May also act as a regulator of adult uterine morphology and function. May also increase apoptosis during ovulation possibly through modulation of FZ1/FZ4/WNT4 signaling. Has phosphaturic effects by specifically inhibiting sodium-dependent phosphate uptake.
• Tissue Specificity: Expressed in mesenchymal cells. Highly expressed in the stroma of proliferative endometrium. Expressed in cardiomyocytes. Shows moderate to strong expression in ovarian tumors with expression increasing as the tumor stage increases. In ovarian tumors, expression levels are inversely correlated with expression of CTNNB1 (at protein level).
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pyle disease	DISJ2YQ3	Strong	Autosomal recessive	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Secreted frizzled-related protein 4 (SFRP4) affects the response to substance of Mitoxantrone.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Secreted frizzled-related protein 4 (SFRP4).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Secreted frizzled-related protein 4 (SFRP4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Secreted frizzled-related protein 4 (SFRP4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Secreted frizzled-related protein 4 (SFRP4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Secreted frizzled-related protein 4 (SFRP4).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Secreted frizzled-related protein 4 (SFRP4).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Secreted frizzled-related protein 4 (SFRP4).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Secreted frizzled-related protein 4 (SFRP4).	[9]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Secreted frizzled-related protein 4 (SFRP4).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Secreted frizzled-related protein 4 (SFRP4).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Secreted frizzled-related protein 4 (SFRP4).	[13]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Perindopril	DMOPZDT	Approved	Perindopril affects the binding of Secreted frizzled-related protein 4 (SFRP4).	[11]
Cyclothiazide	DMJ4AWC	Approved	Cyclothiazide affects the binding of Secreted frizzled-related protein 4 (SFRP4).	[11]

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 increases the methylation of Secreted frizzled-related protein 4 (SFRP4).	[14]

References

• [1] Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease. N Engl J Med. 2016 Jun 30;374(26):2553-2562. doi: 10.1056/NEJMoa1509342.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [11] Computer aided screening of secreted frizzled-related protein 4 (SFRP4): a potential control for diabetes mellitus. Molecules. 2014 Jul 11;19(7):10129-36. doi: 10.3390/molecules190710129.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia. 2004 Jul-Aug;6(4):354-63. doi: 10.1593/neo.03478.
• [14] 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.
• [15] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.