Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRZRT6Q)

• DOT Name: Derlin-3 (DERL3)
• Synonyms: Degradation in endoplasmic reticulum protein 3; DERtrin-3; Der1-like protein 3
• Gene Name: DERL3
• Related Disease:
  Myelodysplastic syndrome
  Acute monocytic leukemia
  Adult acute monocytic leukemia
  Breast cancer
  Breast carcinoma
  DiGeorge syndrome
  Kidney cancer
  Metastatic malignant neoplasm
  Myocardial infarction
  Neoplasm
  Partial deletion of the short arm of chromosome 10
  Renal carcinoma
  Renal cell carcinoma
  Small lymphocytic lymphoma
  Von hippel-lindau disease
  Adult lymphoma
  Chromosomal disorder
  Leukoplakia
  Lymphoma
  Pediatric lymphoma
• UniProt ID: DERL3_HUMAN
• Pfam ID: PF04511
• Sequence:
  MAWQGLAAEFLQVPAVTRAYTAACVLTTAAVQLELLSPFQLYFNPHLVFRKFQVWRLVTN
  FLFFGPLGFSFFFNMLFVFRYCRMLEEGSFRGRTADFVFMFLFGGVLMTLLGLLGSLFFL
  GQALMAMLVYVWSRRSPRVRVNFFGLLTFQAPFLPWALMGFSLLLGNSILVDLLGIAVGH
  IYYFLEDVFPNQPGGKRLLQTPGFLKLLLDAPAEDPNYLPLPEEQPGPHLPPPQQ
• Function: Functional component of endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal glycoproteins, but not that of misfolded nonglycoproteins. May act by forming a channel that allows the retrotranslocation of misfolded glycoproteins into the cytosol where they are ubiquitinated and degraded by the proteasome. May mediate the interaction between VCP and the misfolded glycoproteins. May be involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation.
• Tissue Specificity: Unlike DERL1 and DERL2, restricted to several tissues. Expressed at high levels in placenta, pancreas, spleen and small intestine.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  ABC-family proteins mediated transport (R-HSA-382556)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myelodysplastic syndrome	DISYHNUI	Definitive	Genetic Variation	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[2]
Adult acute monocytic leukemia	DISG6BLX	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
DiGeorge syndrome	DIST1RKO	Strong	Genetic Variation	[4]
Kidney cancer	DISBIPKM	Strong	Biomarker	[5]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[6]
Myocardial infarction	DIS655KI	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Partial deletion of the short arm of chromosome 10	DISET3W3	Strong	Biomarker	[2]
Renal carcinoma	DISER9XT	Strong	Biomarker	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[9]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[10]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Genetic Variation	[11]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[12]
Chromosomal disorder	DISM5BB5	Limited	Genetic Variation	[13]
Leukoplakia	DIST3QD3	Limited	Genetic Variation	[14]
Lymphoma	DISN6V4S	Limited	Biomarker	[12]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[12]

5 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 Derlin-3 (DERL3).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Derlin-3 (DERL3).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Derlin-3 (DERL3).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Derlin-3 (DERL3).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Derlin-3 (DERL3).	[20]

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 increases the methylation of Derlin-3 (DERL3).	[18]

References

• [1] der(3)t(3;5). Another recurring abnormality in myelodysplastic disorder.Cancer Genet Cytogenet. 1991 Jul 1;54(1):129-31. doi: 10.1016/0165-4608(91)90041-r.
• [2] A novel unbalanced whole-arm translocation der(3;10)(q10;q10) in acute monocytic leukemia.Cancer Genet Cytogenet. 2010 Jun;199(2):134-8. doi: 10.1016/j.cancergencyto.2010.02.006.
• [3] Overexpression of Derlin 3 is associated with malignant phenotype of breast cancer cells.Oncol Rep. 2017 Sep;38(3):1760-1766. doi: 10.3892/or.2017.5800. Epub 2017 Jul 10.
• [4] Features of di George syndrome in a child with 45,XX,-3,-22,+der(3),t(3;22)(p25;q11).J Med Genet. 1987 Apr;24(4):225-7. doi: 10.1136/jmg.24.4.225.
• [5] Loss of der(3) in renal carcinoma cells of a patient with constitutional t(3;12).Hum Genet. 1988 Feb;78(2):148-50. doi: 10.1007/BF00278186.
• [6] Unbalanced chromosomal rearrangements in a metastasizing salivary gland tumor with benign histology.Cancer Genet Cytogenet. 1998 Apr 1;102(1):59-64. doi: 10.1016/s0165-4608(97)00301-4.
• [7] Roles for endoplasmic reticulum-associated degradation and the novel endoplasmic reticulum stress response gene Derlin-3 in the ischemic heart.Circ Res. 2010 Feb 5;106(2):307-16. doi: 10.1161/CIRCRESAHA.109.203901. Epub 2009 Nov 25.
• [8] A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect.Nat Commun. 2014 Apr 3;5:3608. doi: 10.1038/ncomms4608.
• [9] Molecular analysis of a familial case of renal cell cancer and a t(3;6)(q12;q15).Genes Chromosomes Cancer. 2001 May;31(1):23-32. doi: 10.1002/gcc.1114.
• [10] Chromosome analyses in chronic lymphocytic leukemia and related B-cell neoplasms.Cancer Genet Cytogenet. 1991 Aug;55(1):49-56. doi: 10.1016/0165-4608(91)90234-l.
• [11] An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation.Am J Hum Genet. 1998 Jun;62(6):1475-83. doi: 10.1086/301888.
• [12] Interphase detection of BCL6/IgH fusion gene in non-Hodgkin lymphoma by fluorescence in situ hybridization.Cancer Genet Cytogenet. 1997 Dec;99(2):102-7. doi: 10.1016/s0165-4608(97)00203-3.
• [13] Molecular cytogenetic characteristics of the human hepatocellular carcinoma cell line HCCLM3 with high metastatic potential: comparative genomic hybridization and multiplex fluorescence in situ hybridization.Cancer Genet Cytogenet. 2005 Apr 15;158(2):180-3. doi: 10.1016/j.cancergencyto.2004.05.010.
• [14] Chromosomal Alterations and Gene Expression Changes Associated with the Progression of Leukoplakia to Advanced Gingivobuccal Cancer.Transl Oncol. 2017 Jun;10(3):396-409. doi: 10.1016/j.tranon.2017.03.008. Epub 2017 Apr 21.
• [15] 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.
• [16] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] 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.
• [19] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [20] 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.