Details of Drug Off-Target (DOT)

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

• DOT Name: Centrosomal protein of 85 kDa-like (CEP85L)
• Synonyms: Serologically defined breast cancer antigen NY-BR-15
• Gene Name: CEP85L
• Related Disease:
  Lissencephaly 10
  Adult glioblastoma
  Advanced cancer
  Atrial fibrillation
  Breast cancer
  Bronchopulmonary dysplasia
  Cardiomyopathy
  Dilated cardiomyopathy 1P
  Glioblastoma multiforme
  Hypertrophic cardiomyopathy
  Lissencephaly due to LIS1 mutation
  Myeloproliferative neoplasm
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Dilated cardiomyopathy
  Anaplastic astrocytoma
  Angiosarcoma
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Melanoma
  Pancreatic cancer
  T-lymphoblastic lymphoma
• UniProt ID: CE85L_HUMAN
• Sequence:
  MWGRFLAPEASGRDSPGGARSFPAGPDYSSAWLPANESLWQATTVPSNHRNNHIRRHSIA
  SDSGDTGIGTSCSDSVEDHSTSSGTLSFKPSQSLITLPTAHVMPSNSSASISKLRESLTP
  DGSKWSTSLMQTLGNHSRGEQDSSLDMKDFRPLRKWSSLSKLTAPDNCGQGGTVCREESR
  NGLEKIGKAKALTSQLRTIGPSCLHDSMEMLRLEDKEINKKRSSTLDCKYKFESCSKEDF
  RASSSTLRRQPVDMTYSALPESKPIMTSSEAFEPPKYLMLGQQAVGGVPIQPSVRTQMWL
  TEQLRTNPLEGRNTEDSYSLAPWQQQQIEDFRQGSETPMQVLTGSSRQSYSPGYQDFSKW
  ESMLKIKEGLLRQKEIVIDRQKQQITHLHERIRDNELRAQHAMLGHYVNCEDSYVASLQP
  QYENTSLQTPFSEESVSHSQQGEFEQKLASTEKEVLQLNEFLKQRLSLFSEEKKKLEEKL
  KTRDRYISSLKKKCQKESEQNKEKQRRIETLEKYLADLPTLDDVQSQSLQLQILEEKNKN
  LQEALIDTEKKLEEIKKQCQDKETQLICQKKKEKELVTTVQSLQQKVERCLEDGIRLPML
  DAKQLQNENDNLRQQNETASKIIDSQQDEIDRMILEIQSMQGKLSKEKLTTQKMMEELEK
  KERNVQRLTKALLENQRQTDETCSLLDQGQEPDQSRQQTVLSKRPLFDLTVIDQLFKEMS
  CCLFDLKALCSILNQRAQGKEPNLSLLLGIRSMNCSAEETENDHSTETLTKKLSDVCQLR
  RDIDELRTTISDRYAQDMGDNCITQ
• Function: Plays an essential role in neuronal cell migration.
• Tissue Specificity: Isoform 1 and isoform 4 are expressed in spleen, lymph, thymus, tonsil and peripheral blood leukocytes, with isoform 1 expressed at higher levels. Isoform 4 is detected in K-562 leukemia cells and in the blood of precursor T lymphoblastic lymphoma (T-ALL) patients.

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lissencephaly 10	DISIS02N	Definitive	Autosomal dominant	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Biomarker	[5]
Cardiomyopathy	DISUPZRG	Strong	CausalMutation	[6]
Dilated cardiomyopathy 1P	DISIWEP5	Strong	CausalMutation	[7]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	CausalMutation	[8]
Lissencephaly due to LIS1 mutation	DISSD2MH	Strong	Autosomal dominant	[1]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Genetic Variation	[9]
Attention deficit hyperactivity disorder	DISL8MX9	moderate	Genetic Variation	[5]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[5]
Dilated cardiomyopathy	DISX608J	moderate	CausalMutation	[10]
Anaplastic astrocytoma	DISSBE0K	Disputed	Biomarker	[4]
Angiosarcoma	DISIYS9W	Disputed	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Disputed	Biomarker	[4]
Colon cancer	DISVC52G	Disputed	Biomarker	[4]
Colon carcinoma	DISJYKUO	Disputed	Biomarker	[4]
Melanoma	DIS1RRCY	Disputed	Biomarker	[4]
Pancreatic cancer	DISJC981	Disputed	Biomarker	[4]
T-lymphoblastic lymphoma	DISGFZXW	Limited	Biomarker	[11]

14 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 Centrosomal protein of 85 kDa-like (CEP85L).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[17]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[17]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Centrosomal protein of 85 kDa-like (CEP85L).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the methylation of Centrosomal protein of 85 kDa-like (CEP85L).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Centrosomal protein of 85 kDa-like (CEP85L).	[23]

References

• [1] Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly. Neuron. 2020 Apr 22;106(2):237-245.e8. doi: 10.1016/j.neuron.2020.01.027. Epub 2020 Feb 24.
• [2] Rare but Recurrent ROS1 Fusions Resulting From Chromosome 6q22 Microdeletions are Targetable Oncogenes in Glioma.Clin Cancer Res. 2018 Dec 15;24(24):6471-6482. doi: 10.1158/1078-0432.CCR-18-1052. Epub 2018 Aug 31.
• [3] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [4] Breakpoint analysis of transcriptional and genomic profiles uncovers novel gene fusions spanning multiple human cancer types.PLoS Genet. 2013 Apr;9(4):e1003464. doi: 10.1371/journal.pgen.1003464. Epub 2013 Apr 25.
• [5] Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis.Biol Psychiatry. 2017 Nov 1;82(9):634-641. doi: 10.1016/j.biopsych.2016.08.040. Epub 2016 Oct 18.
• [6] Targeted sequence capture and GS-FLX Titanium sequencing of 23 hypertrophic and dilated cardiomyopathy genes: implementation into diagnostics.J Med Genet. 2013 Sep;50(9):614-26. doi: 10.1136/jmedgenet-2012-101231. Epub 2013 Jun 19.
• [7] Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.
• [8] Interpreting secondary cardiac disease variants in an exome cohort.Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. doi: 10.1161/CIRCGENETICS.113.000039. Epub 2013 Jul 16.
• [9] Recurrent CEP85L-PDGFRB fusion in patient with t(5;6) and imatinib-responsive myeloproliferative neoplasm with eosinophilia.Leuk Lymphoma. 2013 Jul;54(7):1527-31. doi: 10.3109/10428194.2012.753544. Epub 2013 Jan 28.
• [10] Acute inotropic and lusitropic effects of cardiomyopathic R9C mutation of phospholamban.J Biol Chem. 2015 Mar 13;290(11):7130-40. doi: 10.1074/jbc.M114.630319. Epub 2015 Jan 15.
• [11] Systematic screen for tyrosine kinase rearrangements identifies a novel C6orf204-PDGFRB fusion in a patient with recurrent T-ALL and an associated myeloproliferative neoplasm.Genes Chromosomes Cancer. 2012 Jan;51(1):54-65. doi: 10.1002/gcc.20930. Epub 2011 Sep 21.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes. Environ Toxicol. 2019 Apr;34(4):401-414.
• [21] Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
• [22] 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.
• [23] 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.
• [24] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.