Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSFBT0G)

• DOT Name: Serine protease inhibitor Kazal-type 2 (SPINK2)
• Synonyms: Acrosin-trypsin inhibitor; Epididymis tissue protein Li 172; HUSI-II
• Gene Name: SPINK2
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Azoospermia
  Lymphoma
  Oligospermia
  Spermatogenic failure 29
  Stroke
• UniProt ID: ISK2_HUMAN
• PDB ID: 2JXD; 6KBR
• Pfam ID: PF00050
• Sequence:
  MALSVLRLALLLLAVTFAASLIPQFGLFSKYRTPNCSQYRLPGCPRHFNPVCGSDMSTYA
  NECTLCMKIREGGHNIKIIRNGPC
• Function: As a strong inhibitor of acrosin, it is required for normal spermiogenesis. It probably hinders premature activation of proacrosin and other proteases, thus preventing the cascade of events leading to spermiogenesis defects. May be involved in the regulation of serine protease-dependent germ cell apoptosis. It also inhibits trypsin.
• Tissue Specificity: Expressed in epididymis (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Azoospermia	DIS94181	Strong	Biomarker	[3]
Lymphoma	DISN6V4S	Strong	Altered Expression	[2]
Oligospermia	DIS6YJF3	Strong	Biomarker	[3]
Spermatogenic failure 29	DISKVXZD	Strong	Autosomal recessive	[4]
Stroke	DISX6UHX	moderate	Genetic Variation	[5]

10 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 Serine protease inhibitor Kazal-type 2 (SPINK2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine protease inhibitor Kazal-type 2 (SPINK2).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Serine protease inhibitor Kazal-type 2 (SPINK2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine protease inhibitor Kazal-type 2 (SPINK2).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Serine protease inhibitor Kazal-type 2 (SPINK2).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Serine protease inhibitor Kazal-type 2 (SPINK2).	[10]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Serine protease inhibitor Kazal-type 2 (SPINK2).	[7]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Serine protease inhibitor Kazal-type 2 (SPINK2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine protease inhibitor Kazal-type 2 (SPINK2).	[12]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Serine protease inhibitor Kazal-type 2 (SPINK2).	[13]

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 affects the methylation of Serine protease inhibitor Kazal-type 2 (SPINK2).	[11]

References

• [1] Elevated SPINK2 gene expression is a predictor of poor prognosis in acute myeloid leukemia.Oncol Lett. 2019 Sep;18(3):2877-2884. doi: 10.3892/ol.2019.10665. Epub 2019 Jul 25.
• [2] Identification of trypsin-inhibitory site and structure determination of human SPINK2 serine proteinase inhibitor.Proteins. 2009 Oct;77(1):209-19. doi: 10.1002/prot.22432.
• [3] SPINK2 deficiency causes infertility by inducing sperm defects in heterozygotes and azoospermia inhomozygotes.EMBO Mol Med. 2017 Aug;9(8):1132-1149. doi: 10.15252/emmm.201607461.
• [4] Impaired spermatogenesis and fertility in mice carrying a mutation in the Spink2 gene expressed predominantly in testes. J Biol Chem. 2011 Aug 19;286(33):29108-29117. doi: 10.1074/jbc.M111.244905. Epub 2011 Jun 24.
• [5] Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans.Stroke. 2015 Aug;46(8):2063-8. doi: 10.1161/STROKEAHA.115.009044. Epub 2015 Jun 18.
• [6] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [7] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [8] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] 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.
• [12] 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.
• [13] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.