Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT04AZNZ)

• DOT Name: Coiled-coil domain-containing protein 115 (CCDC115)
• Gene Name: CCDC115
• Related Disease:
  CCDC115-CDG
  Congenital disorder of glycosylation
  Male infertility
  Measles
  Neoplasm
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Wilson disease
  Neuroblastoma
• UniProt ID: CC115_HUMAN
• Pfam ID: PF21730
• Sequence:
  MAALDLRAELDSLVLQLLGDLEELEGKRTVLNARVEEGWLSLAKARYAMGAKSVGPLQYA
  SHMEPQVCLHASEAQEGLQKFKVVRAGVHAPEEVGPREAGLRRRKGPTKTPEPESSEAPQ
  DPLNWFGILVPHSLRQAQASFRDGLQLAADIASLQNRIDWGRSQLRGLQEKLKQLEPGAA
• Function: Accessory component of the proton-transporting vacuolar (V)-ATPase protein pump involved in intracellular iron homeostasis. In aerobic conditions, required for intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation. Necessary for endolysosomal acidification and lysosomal degradation. May be involved in Golgi homeostasis.
• Tissue Specificity: Expressed throughout the brain.
• Reactome Pathway: RHOA GTPase cycle (R-HSA-8980692)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CCDC115-CDG	DISP0LJJ	Strong	Autosomal recessive	[1]
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[2]
Male infertility	DISY3YZZ	Strong	Biomarker	[3]
Measles	DISXSUID	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[5]
Wilson disease	DISVS9H7	Strong	Genetic Variation	[2]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[6]

8 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 Coiled-coil domain-containing protein 115 (CCDC115).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Coiled-coil domain-containing protein 115 (CCDC115).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Coiled-coil domain-containing protein 115 (CCDC115).	[9]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Coiled-coil domain-containing protein 115 (CCDC115).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Coiled-coil domain-containing protein 115 (CCDC115).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Coiled-coil domain-containing protein 115 (CCDC115).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Coiled-coil domain-containing protein 115 (CCDC115).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Coiled-coil domain-containing protein 115 (CCDC115).	[14]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] CCDC115-CDG: A new rare and misleading inherited cause of liver disease.Mol Genet Metab. 2018 Jul;124(3):228-235. doi: 10.1016/j.ymgme.2018.05.002. Epub 2018 May 9.
• [3] Role of Cytosolic Carboxypeptidase 5 in Neuronal Survival and Spermatogenesis.Sci Rep. 2017 Jan 27;7:41428. doi: 10.1038/srep41428.
• [4] Cutting edge: inhibiting measles virus infection but promoting reproduction: an explanation for splicing and tissue-specific expression of CD46.J Immunol. 2002 Nov 15;169(10):5405-9. doi: 10.4049/jimmunol.169.10.5405.
• [5] Modifier locus mapping of a transgenic F2 mouse population identifies CCDC115 as a novel aggressive prostate cancer modifier gene in humans.BMC Genomics. 2018 Jun 11;19(1):450. doi: 10.1186/s12864-018-4827-2.
• [6] Regulation of cell proliferation and apoptosis in neuroblastoma cells by ccp1, a FGF2 downstream gene.BMC Cancer. 2010 Nov 30;10:657. doi: 10.1186/1471-2407-10-657.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.