Details of Drug Off-Target (DOT)

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

• DOT Name: Homeobox protein Nkx-2.1 (NKX2-1)
• Synonyms: Homeobox protein NK-2 homolog A; Thyroid nuclear factor 1; Thyroid transcription factor 1; TTF-1; Thyroid-specific enhancer-binding protein; T/EBP
• Gene Name: NKX2-1
• Related Disease:
  Athyreosis
  Brain-lung-thyroid syndrome
  Carcinoid tumor
  Goiter
  Hereditary progressive chorea without dementia
  Lung neoplasm
  NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction
  Adenoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Central nervous system neoplasm
  Cerebellar ataxia
  Congenital alveolar dysplasia
  Congenital hypothyroidism
  Dystonia
  Endometrial carcinoma
  Epithelial ovarian cancer
  Hypothyroidism
  Medullary thyroid gland carcinoma
  Mesothelioma
  Metastatic malignant neoplasm
  Neuroendocrine cancer
  Non-small-cell lung cancer
  Ovarian cancer
  Pneumonia
  Pneumonitis
  Prostate cancer
  Prostate carcinoma
  Pulmonary disease
  Respiratory disease
  Respiratory failure
  Thyroid cancer
  Thyroid tumor
  Wilms tumor
  Hirschsprung disease
  Neuroendocrine neoplasm
  Tooth agenesis
  Transitional cell carcinoma
  Choreatic disease
  Differentiated thyroid carcinoma
  Episodic kinesigenic dyskinesia 1
  Minimally invasive lung adenocarcinoma
  Movement disorder
• UniProt ID: NKX21_HUMAN
• Pfam ID: PF00046
• Sequence:
  MSMSPKHTTPFSVSDILSPLEESYKKVGMEGGGLGAPLAAYRQGQAAPPTAAMQQHAVGH
  HGAVTAAYHMTAAGVPQLSHSAVGGYCNGNLGNMSELPPYQDTMRNSASGPGWYGANPDP
  RFPAISRFMGPASGMNMSGMGGLGSLGDVSKNMAPLPSAPRRKRRVLFSQAQVYELERRF
  KQQKYLSAPEREHLASMIHLTPTQVKIWFQNHRYKMKRQAKDKAAQQQLQQDSGGGGGGG
  GTGCPQQQQAQQQSPRRVAVPVLVKDGKPCQAGAPAPGAASLQGHAQQQAQHQAQAAQAA
  AAAISVGSGGAGLGAHPGHQPGSAGQSPDLAHHAASPAALQGQVSSLSHLNSSGSDYGTM
  SCSTLLYGRTW
• Function: Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor. Crucial in the maintenance of the thyroid differentiation phenotype. May play a role in lung development and surfactant homeostasis. Forms a regulatory loop with GRHL2 that coordinates lung epithelial cell morphogenesis and differentiation. Activates the transcription of GNRHR and plays a role in enhancing the circadian oscillation of its gene expression. Represses the transcription of the circadian transcriptional repressor NR1D1.
• Tissue Specificity: Thyroid and lung.

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Athyreosis	DISBHHCU	Definitive	Genetic Variation	[1]
Brain-lung-thyroid syndrome	DISSL12Z	Definitive	Autosomal dominant	[2]
Carcinoid tumor	DISMNRDC	Definitive	Biomarker	[3]
Goiter	DISLCGI6	Definitive	Genetic Variation	[4]
Hereditary progressive chorea without dementia	DISW33PR	Definitive	Autosomal dominant	[5]
Lung neoplasm	DISVARNB	Definitive	Altered Expression	[6]
NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction	DISBISW8	Definitive	Autosomal dominant	[7]
Adenoma	DIS78ZEV	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[9]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[9]
Carcinoma	DISH9F1N	Strong	Altered Expression	[10]
Central nervous system neoplasm	DISFC18W	Strong	Biomarker	[11]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[12]
Congenital alveolar dysplasia	DIS1IYUN	Strong	Genetic Variation	[13]
Congenital hypothyroidism	DISL5XVU	Strong	Genetic Variation	[14]
Dystonia	DISJLFGW	Strong	Genetic Variation	[15]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[16]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[17]
Hypothyroidism	DISR0H6D	Strong	Biomarker	[18]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[19]
Mesothelioma	DISKWK9M	Strong	Biomarker	[20]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[21]
Neuroendocrine cancer	DISVGJET	Strong	Biomarker	[22]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[23]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[17]
Pneumonia	DIS8EF3M	Strong	Biomarker	[24]
Pneumonitis	DIS88E0K	Strong	Biomarker	[24]
Prostate cancer	DISF190Y	Strong	Biomarker	[25]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[25]
Pulmonary disease	DIS6060I	Strong	Genetic Variation	[26]
Respiratory disease	DISGGAGJ	Strong	Genetic Variation	[27]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[14]
Thyroid cancer	DIS3VLDH	Strong	Genetic Variation	[28]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[10]
Wilms tumor	DISB6T16	Strong	Biomarker	[29]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[19]
Neuroendocrine neoplasm	DISNPLOO	moderate	Biomarker	[30]
Tooth agenesis	DIS1PWC7	moderate	Biomarker	[13]
Transitional cell carcinoma	DISWVVDR	moderate	Altered Expression	[31]
Choreatic disease	DISH8K3M	Supportive	Autosomal dominant	[32]
Differentiated thyroid carcinoma	DIS1V20Y	Limited	Biomarker	[33]
Episodic kinesigenic dyskinesia 1	DISGVQMP	Limited	Genetic Variation	[34]
Minimally invasive lung adenocarcinoma	DIS4W83X	Limited	Genetic Variation	[35]
Movement disorder	DISOJJ2D	Limited	CausalMutation	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homeobox protein Nkx-2.1 (NKX2-1).	[37]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homeobox protein Nkx-2.1 (NKX2-1).	[38]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homeobox protein Nkx-2.1 (NKX2-1).	[39]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Homeobox protein Nkx-2.1 (NKX2-1).	[40]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Homeobox protein Nkx-2.1 (NKX2-1).	[41]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Homeobox protein Nkx-2.1 (NKX2-1).	[43]

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 Homeobox protein Nkx-2.1 (NKX2-1).	[42]

References

• [1] Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis.Clin Chim Acta. 2017 Jul;470:36-41. doi: 10.1016/j.cca.2017.04.020. Epub 2017 Apr 25.
• [2] Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2-1. J Pediatr. 2004 Aug;145(2):190-3. doi: 10.1016/j.jpeds.2004.04.011.
• [3] Thyroid transcription factor-1 in primary CNS tumors.Appl Immunohistochem Mol Morphol. 2011 Oct;19(5):437-43. doi: 10.1097/PAI.0b013e31820e6baf.
• [4] Mutations in the gene encoding thyroid transcription factor-1 (TTF-1) are not a frequent cause of congenital hypothyroidism (CH) with thyroid dysgenesis.Thyroid. 1997 Jun;7(3):383-7. doi: 10.1089/thy.1997.7.383.
• [5] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [6] Lung recurrence and its therapeutic strategy in patients with pancreatic cancer.Pancreatology. 2020 Jan;20(1):89-94. doi: 10.1016/j.pan.2019.11.015. Epub 2019 Nov 26.
• [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] What's new in pituitary pathology?.Histopathology. 2018 Jan;72(1):133-141. doi: 10.1111/his.13295.
• [9] Expression of thyroid transcription factor-1 is associated with a basal-like phenotype in breast carcinomas.Diagn Pathol. 2013 May 15;8:80. doi: 10.1186/1746-1596-8-80.
• [10] Napsin A Expression in Subtypes of Thyroid Tumors: Comparison with Lung Adenocarcinomas.Endocr Pathol. 2020 Mar;31(1):39-45. doi: 10.1007/s12022-019-09600-6.
• [11] Pituicytoma: Review of commonalities and distinguishing features among TTF-1 positive tumors of the central nervous system.Ann Diagn Pathol. 2017 Aug;29:57-61. doi: 10.1016/j.anndiagpath.2017.05.004. Epub 2017 May 11.
• [12] A novel de novo mutation of the TITF1/NKX2-1 gene causing ataxia, benign hereditary chorea, hypothyroidism and a pituitary mass in a UK family and review of the literature.Cerebellum. 2014 Oct;13(5):588-95. doi: 10.1007/s12311-014-0570-7.
• [13] The Brain-Lung-Thyroid syndrome (BLTS): A novel deletion in chromosome 14q13.2-q21.1 expands the phenotype to humoral immunodeficiency. Eur J Med Genet. 2018 Jul;61(7):393-398. doi: 10.1016/j.ejmg.2018.02.007. Epub 2018 Feb 22.
• [14] Respiratory insufficiency in a newborn with congenital hypothyroidism due to a new mutation of TTF-1/NKX2.1 gene.Pediatr Pulmonol. 2014 Mar;49(3):E42-4. doi: 10.1002/ppul.22788. Epub 2013 Sep 2.
• [15] Clinical differentiation of genetically proven benign hereditary chorea and myoclonus-dystonia.Mov Disord. 2007 Oct 31;22(14):2104-9. doi: 10.1002/mds.21692.
• [16] Value of circulating tumor cells positive for thyroid transcription factor-1 (TTF-1) to predict recurrence and survival rates for endometrial carcinoma.J BUON. 2016 Nov-Dec;21(6):1491-1495.
• [17] Diagnostic Utility of Thyroid Transcription Factor-1 in Ovarian Carcinoma and Its Relationship With Clinicopathologic Prognostic Parameters.Appl Immunohistochem Mol Morphol. 2017 Apr;25(4):237-243. doi: 10.1097/PAI.0000000000000301.
• [18] High-resolution computed tomography findings of thyroid transcription factor 1 deficiency (NKX2-1 mutations).Pediatr Radiol. 2019 Jun;49(7):869-875. doi: 10.1007/s00247-019-04388-3. Epub 2019 Mar 30.
• [19] Expression of Tenascin C, EGFR, E-Cadherin, and TTF-1 in Medullary Thyroid Carcinoma and the Correlation with RET Mutation Status.Int J Mol Sci. 2016 Jul 9;17(7):1093. doi: 10.3390/ijms17071093.
• [20] Biomarkers in the diagnosis of pleural diseases: a 2018 update.Ther Adv Respir Dis. 2018 Jan-Dec;12:1753466618808660. doi: 10.1177/1753466618808660.
• [21] Exploring the spatiotemporal genetic heterogeneity in metastatic lung adenocarcinoma using a nuclei flow-sorting approach.J Pathol. 2019 Feb;247(2):199-213. doi: 10.1002/path.5183. Epub 2018 Dec 28.
• [22] Differentiating Merkel cell carcinoma of lymph nodes without a detectable primary skin tumor from other metastatic neuroendocrine carcinomas: The ELECTHIP criteria.J Am Acad Dermatol. 2018 May;78(5):964-972.e3. doi: 10.1016/j.jaad.2017.11.037. Epub 2017 Nov 24.
• [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] Airway epithelial transcription factor NK2 homeobox 1 inhibits mucous cell metaplasia and Th2 inflammation.Am J Respir Crit Care Med. 2011 Aug 15;184(4):421-9. doi: 10.1164/rccm.201101-0106OC.
• [25] Incidental Finding of Intrathyroid Metastases of Prostatic Cancer on 18F-Choline PET/CT.Clin Nucl Med. 2019 Feb;44(2):e101-e103. doi: 10.1097/RLU.0000000000002374.
• [26] Mutations in the thyroid transcription factor gene NKX2-1 result in decreased expression of SFTPB and SFTPC.Pediatr Res. 2018 Sep;84(3):419-425. doi: 10.1038/pr.2018.30. Epub 2018 Apr 11.
• [27] Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1.Chest. 2013 Sep;144(3):794-804. doi: 10.1378/chest.12-2502.
• [28] Selected single-nucleotide polymorphisms in FOXE1, SERPINA5, FTO, EVPL, TICAM1 and SCARB1 are associated with papillary and follicular thyroid cancer risk: replication study in a German population.Carcinogenesis. 2016 Jul;37(7):677-684. doi: 10.1093/carcin/bgw047. Epub 2016 Apr 28.
• [29] Cystic metastasis of prostate cancer: A case report.Medicine (Baltimore). 2018 Dec;97(50):e13697. doi: 10.1097/MD.0000000000013697.
• [30] Hypothalamic Vasopressin-Producing Tumors: Often Inappropriate Diuresis But Occasionally Cushing Disease.Am J Surg Pathol. 2019 Feb;43(2):251-260. doi: 10.1097/PAS.0000000000001185.
• [31] Primary small cell carcinoma of the ureter: Case report and review of the literature.Medicine (Baltimore). 2018 Jun;97(24):e11113. doi: 10.1097/MD.0000000000011113.
• [32] Benign hereditary chorea: clinical, genetic, and pathological findings. Ann Neurol. 2003 Aug;54(2):244-7. doi: 10.1002/ana.10637.
• [33] Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.Nat Commun. 2017 Jul 13;8:15966. doi: 10.1038/ncomms15966.
• [34] Genetics of Huntington's disease and related disorders.Drug Discov Today. 2014 Jul;19(7):985-9. doi: 10.1016/j.drudis.2014.03.005. Epub 2014 Mar 18.
• [35] Genotype-phenotype correlation in Chinese patients with pulmonary mixed type adenocarcinoma: Relationship between histologic subtypes, TITF-1/SP-A expressions and EGFR mutations.Pathol Res Pract. 2014 Mar;210(3):176-81. doi: 10.1016/j.prp.2013.11.013. Epub 2013 Dec 5.
• [36] Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas.Cancer Sci. 2017 Sep;108(9):1888-1896. doi: 10.1111/cas.13313. Epub 2017 Jul 29.
• [37] Multifaceted suppression of aggressive behavior of thyroid carcinoma by all-trans retinoic acid induced re-differentiation. Mol Cell Endocrinol. 2012 Jan 2;348(1):260-9. doi: 10.1016/j.mce.2011.09.002. Epub 2011 Sep 6.
• [38] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [39] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [40] Epigenetic silencing of TTF-1/NKX2-1 through DNA hypermethylation and histone H3 modulation in thyroid carcinomas. Lab Invest. 2009 Jul;89(7):791-9. doi: 10.1038/labinvest.2009.50. Epub 2009 Jun 8.
• [41] Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth. Mol Cancer Ther. 2013 Jul;12(7):1276-87. doi: 10.1158/1535-7163.MCT-12-0841. Epub 2013 Apr 17.
• [42] 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.
• [43] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.