Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZQ7QJ2)

• DOT Name: Neurogenic differentiation factor 1 (NEUROD1)
• Synonyms: NeuroD; NeuroD1; Class A basic helix-loop-helix protein 3; bHLHa3
• Gene Name: NEUROD1
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Cognitive impairment
  Acute myelogenous leukaemia
  Adenoma
  Alzheimer disease
  Atopic dermatitis
  Colon cancer
  Colon carcinoma
  Epilepsy
  Head-neck squamous cell carcinoma
  Huntington disease
  Hyperglycemia
  Intellectual disability
  Lung adenocarcinoma
  Maturity-onset diabetes of the young type 6
  Medulloblastoma
  Neonatal diabetes mellitus
  Neuroendocrine neoplasm
  Non-small-cell lung cancer
  Obesity
  Pancreatic cancer
  Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome
  Pituitary adenoma
  Prostate cancer
  Prostate carcinoma
  Saethre-Chotzen syndrome
  Schizophrenia
  Small-cell lung cancer
  T-cell acute lymphoblastic leukaemia
  Type-1/2 diabetes
  Asthma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Lung neoplasm
  Monogenic diabetes
  Neuroendocrine cancer
  Small lymphocytic lymphoma
  Maturity-onset diabetes of the young
  Colorectal carcinoma
  Gastric cancer
  Nervous system disease
  Neuroblastoma
  Pitt-Hopkins syndrome
  Retinitis pigmentosa
  Stomach cancer
• UniProt ID: NDF1_HUMAN
• Pfam ID: PF00010 ; PF12533
• Sequence:
  MTKSYSESGLMGEPQPQGPPSWTDECLSSQDEEHEADKKEDDLETMNAEEDSLRNGGEEE
  DEDEDLEEEEEEEEEDDDQKPKRRGPKKKKMTKARLERFKLRRMKANARERNRMHGLNAA
  LDNLRKVVPCYSKTQKLSKIETLRLAKNYIWALSEILRSGKSPDLVSFVQTLCKGLSQPT
  TNLVAGCLQLNPRTFLPEQNQDMPPHLPTASASFPVHPYSYQSPGLPSPPYGTMDSSHVF
  HVKPPPHAYSAALEPFFESPLTDCTSPSFDGPLSPPLSINGNFSFKHEPSAEFEKNYAFT
  MHYPAATLAGAQSHGSIFSGTAAPRCEIPIDNIMSFDSHSHHERVMSAQLNAIFHD
• Function: Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5'-CANNTG-3'. Associates with the p300/CBP transcription coactivator complex to stimulate transcription of the secretin gene as well as the gene encoding the cyclin-dependent kinase inhibitor CDKN1A. Contributes to the regulation of several cell differentiation pathways, like those that promote the formation of early retinal ganglion cells, inner ear sensory neurons, granule cells forming either the cerebellum or the dentate gyrus cell layer of the hippocampus, endocrine islet cells of the pancreas and enteroendocrine cells of the small intestine. Together with PAX6 or SIX3, is required for the regulation of amacrine cell fate specification. Also required for dendrite morphogenesis and maintenance in the cerebellar cortex. Associates with chromatin to enhancer regulatory elements in genes encoding key transcriptional regulators of neurogenesis.
• KEGG Pathway: Maturity onset diabetes of the young (hsa04950)
• Reactome Pathway:
  Regulation of gene expression in endocrine-committed (NEUROG3+) progenitor cells (R-HSA-210746)
  Regulation of gene expression in beta cells (R-HSA-210745)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Altered Expression	[1]
Cervical carcinoma	DIST4S00	Definitive	Altered Expression	[1]
Cognitive impairment	DISH2ERD	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adenoma	DIS78ZEV	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[5]
Atopic dermatitis	DISTCP41	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Epilepsy	DISBB28L	Strong	Biomarker	[8]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Posttranslational Modification	[9]
Huntington disease	DISQPLA4	Strong	Biomarker	[10]
Hyperglycemia	DIS0BZB5	Strong	Biomarker	[11]
Intellectual disability	DISMBNXP	Strong	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[12]
Maturity-onset diabetes of the young type 6	DISANGXI	Strong	Autosomal recessive	[13]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[14]
Neonatal diabetes mellitus	DISFHF9K	Strong	Genetic Variation	[15]
Neuroendocrine neoplasm	DISNPLOO	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[16]
Obesity	DIS47Y1K	Strong	Genetic Variation	[17]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[18]
Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome	DIS4HC21	Strong	Autosomal recessive	[13]
Pituitary adenoma	DISJ5R1X	Strong	Altered Expression	[19]
Prostate cancer	DISF190Y	Strong	Altered Expression	[20]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[20]
Saethre-Chotzen syndrome	DIS3A437	Strong	Biomarker	[21]
Schizophrenia	DISSRV2N	Strong	Biomarker	[22]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[23]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[24]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[25]
Asthma	DISW9QNS	moderate	Genetic Variation	[26]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[27]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[27]
Carcinoma	DISH9F1N	moderate	Biomarker	[28]
Lung neoplasm	DISVARNB	moderate	Biomarker	[28]
Monogenic diabetes	DISEB8Q0	Moderate	Autosomal recessive	[29]
Neuroendocrine cancer	DISVGJET	moderate	Altered Expression	[30]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[31]
Maturity-onset diabetes of the young	DISG75M5	Supportive	Autosomal dominant	[32]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[14]
Gastric cancer	DISXGOUK	Limited	Biomarker	[33]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[34]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[14]
Pitt-Hopkins syndrome	DISM1JID	Limited	Genetic Variation	[35]
Retinitis pigmentosa	DISCGPY8	Limited	Autosomal recessive	[15]
Stomach cancer	DISKIJSX	Limited	Biomarker	[33]

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 Neurogenic differentiation factor 1 (NEUROD1).	[36]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neurogenic differentiation factor 1 (NEUROD1).	[37]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Neurogenic differentiation factor 1 (NEUROD1).	[38]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Neurogenic differentiation factor 1 (NEUROD1).	[39]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Neurogenic differentiation factor 1 (NEUROD1).	[40]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Neurogenic differentiation factor 1 (NEUROD1).	[42]

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 decreases the methylation of Neurogenic differentiation factor 1 (NEUROD1).	[41]

References

• [1] Correlation of TWIST2 up-regulation and epithelial-mesenchymal transition during tumorigenesis and progression of cervical carcinoma.Gynecol Oncol. 2012 Jan;124(1):112-8. doi: 10.1016/j.ygyno.2011.09.003. Epub 2011 Oct 22.
• [2] The Intellectual Disability and Schizophrenia Associated Transcription Factor TCF4 Is Regulated by Neuronal Activity and Protein Kinase A.J Neurosci. 2017 Oct 25;37(43):10516-10527. doi: 10.1523/JNEUROSCI.1151-17.2017. Epub 2017 Sep 26.
• [3] The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia.Nat Commun. 2018 Apr 24;9(1):1622. doi: 10.1038/s41467-018-03854-0.
• [4] Analysis of pituitary adenoma expression patterns suggests a potential role for the NeuroD1 transcription factor in neuroendocrine tumor-targeting therapies.Oncotarget. 2019 Jan 8;10(3):289-312. doi: 10.18632/oncotarget.26513. eCollection 2019 Jan 8.
• [5] Valproic Acid Stimulates Hippocampal Neurogenesis via Activating the Wnt/-Catenin Signaling Pathway in the APP/PS1/Nestin-GFP Triple Transgenic Mouse Model of Alzheimer's Disease.Front Aging Neurosci. 2019 Mar 26;11:62. doi: 10.3389/fnagi.2019.00062. eCollection 2019.
• [6] Activation of RhoA, Smad2, c-Src, PKC-II/ and JNK in atopic dermatitis.Australas J Dermatol. 2018 Nov;59(4):e258-e261. doi: 10.1111/ajd.12801. Epub 2018 Mar 2.
• [7] Protein kinase C beta II suppresses colorectal cancer by regulating IGF-1 mediated cell survival.Oncotarget. 2016 Apr 12;7(15):20919-33. doi: 10.18632/oncotarget.8062.
• [8] Mice with conditional NeuroD1 knockout display reduced aberrant hippocampal neurogenesis but no change in epileptic seizures.Exp Neurol. 2017 Jul;293:190-198. doi: 10.1016/j.expneurol.2017.04.005. Epub 2017 Apr 18.
• [9] Hypermethylation of the retinoic acid receptor-beta(2) gene in head and neck carcinogenesis.Clin Cancer Res. 2004 Mar 1;10(5):1733-42. doi: 10.1158/1078-0432.ccr-0989-3.
• [10] Early down-regulation of PKC as a pro-survival mechanism in Huntington's disease.Neuromolecular Med. 2014 Mar;16(1):25-37. doi: 10.1007/s12017-013-8248-8. Epub 2013 Jul 30.
• [11] Genetic Dissection and Clinical Features of MODY6 (NEUROD1-MODY).Curr Diab Rep. 2019 Feb 22;19(3):12. doi: 10.1007/s11892-019-1130-9.
• [12] Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non-small cell lung cancer.Mol Cancer Res. 2013 Apr;11(4):329-38. doi: 10.1158/1541-7786.MCR-12-0456. Epub 2013 Jan 30.
• [13] 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.
• [14] Neurogenic differentiation factor 1 promotes colorectal cancer cell proliferation and tumorigenesis by suppressing the p53/p21 axis.Cancer Sci. 2020 Jan;111(1):175-185. doi: 10.1111/cas.14233. Epub 2019 Dec 10.
• [15] A homozygous missense mutation in NEUROD1 is associated with nonsyndromic autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2014 Dec 4;56(1):150-5. doi: 10.1167/iovs.14-15382.
• [16] Specific -tubulin isotypes can functionally enhance or diminish epothilone B sensitivity in non-small cell lung cancer cells.PLoS One. 2011;6(6):e21717. doi: 10.1371/journal.pone.0021717. Epub 2011 Jun 29.
• [17] Autosomal inheritance of diabetes in two families characterized by obesity and a novel H241Q mutation in NEUROD1.Pediatr Diabetes. 2008 Aug;9(4 Pt 2):367-72. doi: 10.1111/j.1399-5448.2008.00379.x. Epub 2008 Mar 5.
• [18] Twist, a novel oncogene, is upregulated in pancreatic cancer: clinical implication of Twist expression in pancreatic juice.Int J Cancer. 2007 Apr 15;120(8):1634-40. doi: 10.1002/ijc.22295.
• [19] Differential expression of neurogenins and NeuroD1 in human pituitary tumours.J Endocrinol. 2007 Sep;194(3):475-84. doi: 10.1677/JOE-07-0020.
• [20] NeuroD1 expression in human prostate cancer: can it contribute to neuroendocrine differentiation comprehension?.Eur Urol. 2007 Nov;52(5):1365-73. doi: 10.1016/j.eururo.2006.11.030. Epub 2006 Nov 20.
• [21] Contiguous gene deletion neighboring TWIST1 identified in a patient with Saethre-Chotzen syndrome associated with neurodevelopmental delay: Possible contribution of HDAC9.Congenit Anom (Kyoto). 2018 Jan;58(1):33-35. doi: 10.1111/cga.12216. Epub 2017 May 2.
• [22] The early growth response protein 1-miR-30a-5p-neurogenic differentiation factor 1 axis as a novel biomarker for schizophrenia diagnosis and treatment monitoring.Transl Psychiatry. 2017 Jan 10;7(1):e998. doi: 10.1038/tp.2016.268.
• [23] Comparative analysis of TTF-1 binding DNA regions in small-cell lung cancer and non-small-cell lung cancer.Mol Oncol. 2020 Feb;14(2):277-293. doi: 10.1002/1878-0261.12608. Epub 2019 Dec 15.
• [24] Oncogenic potential of the transcription factor LYL1 in acute myeloblastic leukemia. Leukemia. 2005 Nov;19(11):1941-7. doi: 10.1038/sj.leu.2403836.
• [25] Murine Perinatal -Cell Proliferation and the Differentiation of Human Stem Cell-Derived Insulin-Expressing Cells Require NEUROD1.Diabetes. 2019 Dec;68(12):2259-2271. doi: 10.2337/db19-0117. Epub 2019 Sep 13.
• [26] Pharmacogenetics of 2 adrenergic receptor gene polymorphisms, long-acting -agonists and asthma.Clin Exp Allergy. 2011 Mar;41(3):312-26. doi: 10.1111/j.1365-2222.2011.03696.x.
• [27] miR-151-3p Targets TWIST1 to Repress Migration of Human Breast Cancer Cells.PLoS One. 2016 Dec 8;11(12):e0168171. doi: 10.1371/journal.pone.0168171. eCollection 2016.
• [28] NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM.Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6524-9. doi: 10.1073/pnas.1303932110. Epub 2013 Apr 3.
• [29] 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.
• [30] The expression of NeuroD and mASH1 in the gastroenteropancreatic neuroendocrine tumors.Mod Pathol. 2008 Nov;21(11):1363-70. doi: 10.1038/modpathol.2008.121. Epub 2008 Jun 27.
• [31] Protein kinase c--dependent activation of NF-B in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo.Cancer Cell. 2013 Jan 14;23(1):77-92. doi: 10.1016/j.ccr.2012.12.003.
• [32] Review on monogenic diabetes. Curr Opin Endocrinol Diabetes Obes. 2011 Aug;18(4):252-8. doi: 10.1097/MED.0b013e3283488275.
• [33] miR-374a-5p: A New Target for Diagnosis and Drug Resistance Therapy in Gastric Cancer.Mol Ther Nucleic Acids. 2019 Dec 6;18:320-331. doi: 10.1016/j.omtn.2019.07.025. Epub 2019 Aug 27.
• [34] A 3-dimensional human embryonic stem cell (hESC)-derived model to detect developmental neurotoxicity of nanoparticles.Arch Toxicol. 2013 Apr;87(4):721-33. doi: 10.1007/s00204-012-0984-2. Epub 2012 Dec 2.
• [35] Partial deletion of TCF4 in three generation family with non-syndromic intellectual disability, without features of Pitt-Hopkins syndrome.Eur J Med Genet. 2016 Jun;59(6-7):310-4. doi: 10.1016/j.ejmg.2016.04.003. Epub 2016 Apr 28.
• [36] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [37] Differentiating human NT2/D1 neurospheres as a versatile in vitro 3D model system for developmental neurotoxicity testing. Toxicology. 2008 Jul 30;249(2-3):243-50. doi: 10.1016/j.tox.2008.05.014. Epub 2008 Jul 2.
• [38] 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.
• [39] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [40] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [41] 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.
• [42] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.