Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSE1YM5)

• DOT Name: Coiled-coil domain-containing protein 50 (CCDC50)
• Synonyms: Protein Ymer
• Gene Name: CCDC50
• Related Disease:
  Acute myelogenous leukaemia
  Autosomal dominant nonsyndromic hearing loss 44
  Autosomal dominant optic atrophy
  Autosomal dominant optic atrophy, classic form
  Blastic plasmacytoid dendritic cell neoplasm
  Deafness
  Hepatocellular carcinoma
  Mantle cell lymphoma
  Small lymphocytic lymphoma
  Autosomal dominant nonsyndromic hearing loss
  Nonsyndromic genetic hearing loss
• UniProt ID: CCD50_HUMAN
• PDB ID: 6LAN
• Pfam ID: PF15295
• Sequence:
  MAEVSIDQSKLPGVKEVCRDFAVLEDHTLAHSLQEQEIEHHLASNVQRNRLVQHDLQVAK
  QLQEEDLKAQAQLQKRYKDLEQQDCEIAQEIQEKLAIEAERRRIQEKKDEDIARLLQEKE
  LQEEKKRKKHFPEFPATRAYADSYYYEDGGMKPRVMKEAVSTPSRMAHRDQEWYDAEIAR
  KLQEEELLATQVDMRAAQVAQDEEIARLLMAEEKKAYKKAKEREKSSLDKRKQDPEWKPK
  TAKAANSKSKESDEPHHSKNERPARPPPPIMTDGEDADYTHFTNQQSSTRHFSKSESSHK
  GFHYKH
• Function: Involved in EGFR signaling.
• Tissue Specificity: Isoform 1 and isoform 2 are coexpressed in placenta, liver, lung, kidney and pancreas. Only isoform 1 is detected in skeletal muscle, brain and heart.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Autosomal dominant nonsyndromic hearing loss 44	DIS0NETF	Strong	Autosomal dominant	[2]
Autosomal dominant optic atrophy	DISOCR1N	Strong	Genetic Variation	[3]
Autosomal dominant optic atrophy, classic form	DISXUAV9	Strong	Genetic Variation	[3]
Blastic plasmacytoid dendritic cell neoplasm	DISLEJU7	Strong	Altered Expression	[1]
Deafness	DISKCLH4	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Mantle cell lymphoma	DISFREOV	moderate	Biomarker	[5]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[5]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[6]
Nonsyndromic genetic hearing loss	DISZX61P	Limited	Autosomal dominant	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Coiled-coil domain-containing protein 50 (CCDC50).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the ubiquitination of Coiled-coil domain-containing protein 50 (CCDC50).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Coiled-coil domain-containing protein 50 (CCDC50).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Coiled-coil domain-containing protein 50 (CCDC50).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Coiled-coil domain-containing protein 50 (CCDC50).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[16]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[17]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[23]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Coiled-coil domain-containing protein 50 (CCDC50).	[24]

References

• [1] Features of non-activation dendritic state and immune deficiency in blastic plasmacytoid dendritic cell neoplasm (BPDCN).Blood Cancer J. 2019 Dec 6;9(12):99. doi: 10.1038/s41408-019-0262-0.
• [2] A mutation in CCDC50, a gene encoding an effector of epidermal growth factor-mediated cell signaling, causes progressive hearing loss. Am J Hum Genet. 2007 Jun;80(6):1076-89. doi: 10.1086/518311. Epub 2007 Apr 24.
• [3] A 9.3 Mb microdeletion of 3q27.3q29 associated with psychomotor and growth delay, tricuspid valve dysplasia and bifid thumb.Eur J Med Genet. 2009 Mar-Jun;52(2-3):131-3. doi: 10.1016/j.ejmg.2009.03.009. Epub 2009 Mar 24.
• [4] A Coiled-Coil Domain Containing 50 Splice Variant Is Modulated by Serine/Arginine-Rich Splicing Factor 3 and Promotes Hepatocellular Carcinoma in Mice by the Ras Signaling Pathway.Hepatology. 2019 Jan;69(1):179-195. doi: 10.1002/hep.30147. Epub 2018 Dec 22.
• [5] Gene knockdown studies revealed CCDC50 as a candidate gene in mantle cell lymphoma and chronic lymphocytic leukemia.Leukemia. 2009 Nov;23(11):2018-26. doi: 10.1038/leu.2009.144. Epub 2009 Jul 30.
• [6] Genetic Hearing Loss Overview. 1999 Feb 14 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [7] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
• [16] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [17] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [18] 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.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [22] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [23] 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.
• [24] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.