Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHTCW94)

• DOT Name: Serine protease inhibitor Kazal-type 4 (SPINK4)
• Synonyms: Peptide PEC-60 homolog
• Gene Name: SPINK4
• Related Disease:
  Advanced cancer
  Barrett esophagus
  Coeliac disease
  Metabolic disorder
  Non-insulin dependent diabetes
  Obesity
  Acute myelogenous leukaemia
  Pancreatic cancer
  ACTH-independent macronodular adrenal hyperplasia 1
  Brooke-Spiegler syndrome
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Neuroendocrine neoplasm
  Short bowel syndrome
• UniProt ID: ISK4_HUMAN
• Pfam ID: PF00050
• Sequence:
  MAVRQWVIALALAALLVVDREVPVAAGKLPFSRMPICEHMVESPTCSQMSNLVCGTDGLT
  YTNECQLCLARIKTKQDIQIMKDGKC

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[2]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[3]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[6]
Pancreatic cancer	DISJC981	moderate	Biomarker	[7]
ACTH-independent macronodular adrenal hyperplasia 1	DISH2YV8	Limited	Biomarker	[8]
Brooke-Spiegler syndrome	DIS36OT6	Limited	Biomarker	[9]
Colon cancer	DISVC52G	Limited	Altered Expression	[10]
Colon carcinoma	DISJYKUO	Limited	Altered Expression	[10]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[10]
Neuroendocrine neoplasm	DISNPLOO	Limited	Altered Expression	[11]
Short bowel syndrome	DISMB5FU	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine protease inhibitor Kazal-type 4 (SPINK4).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Serine protease inhibitor Kazal-type 4 (SPINK4).	[13]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Serine protease inhibitor Kazal-type 4 (SPINK4).	[14]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Serine protease inhibitor Kazal-type 4 (SPINK4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine protease inhibitor Kazal-type 4 (SPINK4).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Octanal	DMTN0OK	Investigative	Octanal increases the methylation of Serine protease inhibitor Kazal-type 4 (SPINK4).	[17]

References

• [1] Wild-type and splice-variant secretin receptors in lung cancer: overexpression in carcinoid tumors and peritumoral lung tissue.Mod Pathol. 2008 Apr;21(4):387-95. doi: 10.1038/modpathol.3801005. Epub 2008 Jan 25.
• [2] Single cell RNA-seq reveals profound transcriptional similarity between Barrett's oesophagus and oesophageal submucosal glands.Nat Commun. 2018 Oct 15;9(1):4261. doi: 10.1038/s41467-018-06796-9.
• [3] The SPINK gene family and celiac disease susceptibility.Immunogenetics. 2007 May;59(5):349-57. doi: 10.1007/s00251-007-0199-5. Epub 2007 Feb 27.
• [4] Potent antiobesity effect of a short-length peptide YY-analogue continuously administered in mice.Bioorg Med Chem Lett. 2017 Aug 15;27(16):3829-3832. doi: 10.1016/j.bmcl.2017.06.055. Epub 2017 Jun 23.
• [5] Intestinal peptide changes after bariatric and minimally invasive surgery: Relation to diabetes remission.Peptides. 2018 Feb;100:114-122. doi: 10.1016/j.peptides.2017.12.010.
• [6] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [7] Gastrin vaccine improves response to immune checkpoint antibody in murine pancreatic cancer by altering the tumor microenvironment.Cancer Immunol Immunother. 2019 Oct;68(10):1635-1648. doi: 10.1007/s00262-019-02398-6. Epub 2019 Sep 24.
• [8] Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators.Oncogene. 2004 Feb 26;23(8):1575-85. doi: 10.1038/sj.onc.1207277.
• [9] Novel GLP-1/GLP-2 co-agonists display marked effects on gut volume and improves glycemic control in mice.Physiol Behav. 2018 Aug 1;192:72-81. doi: 10.1016/j.physbeh.2018.03.004. Epub 2018 Mar 11.
• [10] Association and diagnostic value of serum SPINK4 in colorectal cancer.PeerJ. 2019 Apr 4;7:e6679. doi: 10.7717/peerj.6679. eCollection 2019.
• [11] Glucose-dependent insulinotropic polypeptide receptors in most gastroenteropancreatic and bronchial neuroendocrine tumors.J Clin Endocrinol Metab. 2012 Feb;97(2):482-8. doi: 10.1210/jc.2011-2454. Epub 2011 Nov 23.
• [12] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [13] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [14] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [15] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [16] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [17] DNA Methylome Analysis of Saturated Aliphatic Aldehydes in Pulmonary Toxicity. Sci Rep. 2018 Jul 12;8(1):10497. doi: 10.1038/s41598-018-28813-z.