Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWS7DED)

• DOT Name: Dickkopf-like protein 1 (DKKL1)
• Synonyms: Cancer/testis antigen 34; CT34; Protein soggy-1; SGY-1
• Gene Name: DKKL1
• Related Disease:
  Cryptorchidism
  Male infertility
  Multiple sclerosis
  Female hypogonadism
• UniProt ID: DKKL1_HUMAN
• Sequence:
  MGEASPPAPARRHLLVLLLLLSTLVIPSAAAPIHDADAQESSLGLTGLQSLLQGFSRLFL
  KGNLLRGIDSLFSAPMDFRGLPGNYHKEENQEHQLGNNTLSSHLQIDKMTDNKTGEVLIS
  ENVVASIQPAEGSFEGDLKVPRMEEKEALVPIQKATDSFHTELHPRVAFWIIKLPRRRSH
  QDALEGGHWLSEKRHRLQAIRDGLRKGTHKDVLEEGTESSSHSRLSPRKTHLLYILRPSR
  QL
• Function: Involved in fertilization by facilitating sperm penetration of the zona pellucida. May promote spermatocyte apoptosis, thereby limiting sperm production. In adults, may reduce testosterone synthesis in Leydig cells. Is not essential either for development or fertility.
• Tissue Specificity: More highly expressed in adult testis than in fetal testis. Exclusively expressed in the testis (at protein level). Intense expression in stages II, III and IV of spermatogenesis, whereas expression is lower in stage I.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cryptorchidism	DISYUD2P	Strong	Biomarker	[1]
Male infertility	DISY3YZZ	Strong	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[2]
Female hypogonadism	DISWASB4	Limited	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Dickkopf-like protein 1 (DKKL1).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Dickkopf-like protein 1 (DKKL1).	[5]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Dickkopf-like protein 1 (DKKL1).	[6]
Fenfluramine	DM0762O	Phase 3	Fenfluramine increases the expression of Dickkopf-like protein 1 (DKKL1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dickkopf-like protein 1 (DKKL1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dickkopf-like protein 1 (DKKL1).	[9]

References

• [1] Developmental expression and function of DKKL1/Dkkl1 in humans and mice.Reprod Biol Endocrinol. 2012 Jul 21;10:51. doi: 10.1186/1477-7827-10-51.
• [2] Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.Nat Genet. 2013 Nov;45(11):1353-60. doi: 10.1038/ng.2770. Epub 2013 Sep 29.
• [3] Serum biomarker analysis in patients with premature ovarian insufficiency.Cytokine. 2020 Feb;126:154876. doi: 10.1016/j.cyto.2019.154876. Epub 2019 Oct 16.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [7] Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. Pulm Circ. 2011 Jul-Sep;1(3):405-18. doi: 10.4103/2045-8932.87310.
• [8] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [9] 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.