Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW58FG4)

• DOT Name: T-box transcription factor TBX4 (TBX4)
• Synonyms: T-box protein 4
• Gene Name: TBX4
• Related Disease:
  Coxopodopatellar syndrome
  Lung cancer
  Lung carcinoma
  Pulmonary arterial hypertension
  Advanced cancer
  Anxiety
  Anxiety disorder
  Chronic obstructive pulmonary disease
  Clubfoot
  Colorectal carcinoma
  Congenital diaphragmatic hernia
  Congenital vertical talus
  Depression
  Genitopatellar syndrome
  High blood pressure
  Hyperparathyroidism
  Neoplasm
  Post-traumatic stress disorder
  Respiratory failure
  Social phobia
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Pulmonary disease
  Heritable pulmonary arterial hypertension
  Psychotic disorder
  Schizophrenia
• UniProt ID: TBX4_HUMAN
• Pfam ID: PF00907
• Sequence:
  MLQDKGLSESEEAFRAPGPALGEASAANAPEPALAAPGLSGAALGSPPGPGADVVAAAAA
  EQTIENIKVGLHEKELWKKFHEAGTEMIITKAGRRMFPSYKVKVTGMNPKTKYILLIDIV
  PADDHRYKFCDNKWMVAGKAEPAMPGRLYVHPDSPATGAHWMRQLVSFQKLKLTNNHLDP
  FGHIILNSMHKYQPRLHIVKADENNAFGSKNTAFCTHVFPETSFISVTSYQNHKITQLKI
  ENNPFAKGFRGSDDSDLRVARLQSKEYPVISKSIMRQRLISPQLSATPDVGPLLGTHQAL
  QHYQHENGAHSQLAEPQDLPLSTFPTQRDSSLFYHCLKRRDGTRHLDLPCKRSYLEAPSS
  VGEDHYFRSPPPYDQQMLSPSYCSEVTPREACMYSGSGPEIAGVSGVDDLPPPPLSCNMW
  TSVSPYTSYSVQTMETVPYQPFPTHFTATTMMPRLPTLSAQSSQPPGNAHFSVYNQLSQS
  QVRERGPSASFPRERGLPQGCERKPPSPHLNAANEFLYSQTFSLSRESSLQYHSGMGTVE
  NWTDG
• Function: Transcriptional regulator that has an essential role in the organogenesis of lungs, pelvis, and hindlimbs.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coxopodopatellar syndrome	DISMJAT7	Definitive	Autosomal dominant	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[2]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[2]
Pulmonary arterial hypertension	DISP8ZX5	Definitive	Autosomal dominant	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Anxiety	DISIJDBA	Strong	Biomarker	[5]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[5]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[6]
Clubfoot	DISLXT4S	Strong	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Altered Expression	[9]
Congenital vertical talus	DISZF3HD	Strong	Genetic Variation	[10]
Depression	DIS3XJ69	Strong	Biomarker	[11]
Genitopatellar syndrome	DIS5E2L7	Strong	Biomarker	[12]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[13]
Hyperparathyroidism	DIS4FVAT	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Post-traumatic stress disorder	DISHL1EY	Strong	Biomarker	[15]
Respiratory failure	DISVMYJO	Strong	Genetic Variation	[16]
Social phobia	DISQGN78	Strong	Biomarker	[17]
Matthew-Wood syndrome	DISA7HR7	moderate	Altered Expression	[18]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Altered Expression	[18]
Pulmonary disease	DIS6060I	moderate	Genetic Variation	[19]
Heritable pulmonary arterial hypertension	DISD1Y94	Supportive	Autosomal dominant	[20]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[21]
Schizophrenia	DISSRV2N	Limited	Biomarker	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of T-box transcription factor TBX4 (TBX4).	[22]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of T-box transcription factor TBX4 (TBX4).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of T-box transcription factor TBX4 (TBX4).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of T-box transcription factor TBX4 (TBX4).	[24]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of T-box transcription factor TBX4 (TBX4).	[23]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of T-box transcription factor TBX4 (TBX4).	[25]

References

• [1] The small patella syndrome: description of five cases from three families and examination of possible allelism with familial patella aplasia-hypoplasia and nail-patella syndrome. J Med Genet. 2001 Mar;38(3):209-14. doi: 10.1136/jmg.38.3.209.
• [2] Chemical identification of a sulfated glucan from Antrodia cinnamomea and its anti-cancer functions via inhibition of EGFR and mTOR activity.Carbohydr Polym. 2018 Dec 15;202:536-544. doi: 10.1016/j.carbpol.2018.09.009. Epub 2018 Sep 6.
• [3] 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.
• [4] Oral Submucous Fibrosis as an Overhealing Wound: Implications in Malignant Transformation.Recent Pat Anticancer Drug Discov. 2018;13(3):272-291. doi: 10.2174/1574892813666180227103147.
• [5] Single prolonged stress PTSD model triggers progressive severity of anxiety, altered gene expression in locus coeruleus and hypothalamus and effected sensitivity to NPY.Eur Neuropsychopharmacol. 2019 Apr;29(4):482-492. doi: 10.1016/j.euroneuro.2019.02.010. Epub 2019 Mar 14.
• [6] A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.BMC Genet. 2015 Dec 3;16:138. doi: 10.1186/s12863-015-0299-4.
• [7] Genetics of clubfoot; recent progress and future perspectives.Eur J Med Genet. 2018 Feb;61(2):107-113. doi: 10.1016/j.ejmg.2017.09.006. Epub 2017 Sep 14.
• [8] Glucuronorhamnoxylan from Capsosiphon fulvescens inhibits the growth of HT-29 human colon cancer cells in vitro and in vivo via induction of apoptotic cell death.Int J Biol Macromol. 2019 Mar 1;124:1060-1068. doi: 10.1016/j.ijbiomac.2018.12.001. Epub 2018 Dec 3.
• [9] Expression of T-box transcription factors 2, 4 and 5 is decreased in the branching airway mesenchyme of nitrofen-induced hypoplastic lungs.Pediatr Surg Int. 2017 Feb;33(2):139-143. doi: 10.1007/s00383-016-4005-z. Epub 2016 Nov 11.
• [10] The 2017 ABJS Nicolas Andry Award: Advancing Personalized Medicine for Clubfoot Through Translational Research.Clin Orthop Relat Res. 2017 Jun;475(6):1716-1725. doi: 10.1007/s11999-017-5290-0. Epub 2017 Feb 24.
• [11] Factors Associated With Presenteeism at Work in Type 2 Diabetes Mellitus.J Occup Environ Med. 2018 Dec;60(12):1116-1119. doi: 10.1097/JOM.0000000000001446.
• [12] Genitopatellar syndrome: expanding the phenotype and excluding mutations in LMX1B and TBX4.Am J Med Genet A. 2006 Jul 15;140(14):1567-72. doi: 10.1002/ajmg.a.31258.
• [13] Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity.Clin Genet. 2019 Oct;96(4):366-370. doi: 10.1111/cge.13605. Epub 2019 Jul 22.
• [14] Compared effects of calcium and sodium polystyrene sulfonate on mineral and bone metabolism and volume overload in pre-dialysis patients with hyperkalemia.Clin Exp Nephrol. 2018 Feb;22(1):35-44. doi: 10.1007/s10157-017-1412-y. Epub 2017 Apr 18.
• [15] Hyperbaric oxygen therapy restored traumatic stress-induced dysregulation of fear memory and related neurochemical abnormalities.Behav Brain Res. 2019 Feb 1;359:861-870. doi: 10.1016/j.bbr.2018.07.014. Epub 2018 Jul 26.
• [16] Identification of a deletion containing TBX4 in a neonate with acinar dysplasia by rapid exome sequencing.Am J Med Genet A. 2019 May;179(5):842-845. doi: 10.1002/ajmg.a.61096. Epub 2019 Mar 3.
• [17] Factors associated with social anxiety in South Korean adults with epilepsy.Epilepsy Behav. 2019 Dec;101(Pt A):106569. doi: 10.1016/j.yebeh.2019.106569. Epub 2019 Oct 30.
• [18] Low expression of TBX4 predicts poor prognosis in patients with stage II pancreatic ductal adenocarcinoma.Int J Mol Sci. 2011;12(8):4953-63. doi: 10.3390/ijms12084953. Epub 2011 Aug 3.
• [19] Neonatal Lung Disease Associated with TBX4 Mutations.J Pediatr. 2019 Mar;206:286-292.e1. doi: 10.1016/j.jpeds.2018.10.018. Epub 2018 Nov 7.
• [20] Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet. 2013 May;45(5):518-21. doi: 10.1038/ng.2581. Epub 2013 Mar 17.
• [21] Sex-specific rates of transmission of psychosis in the New England high-risk family study.Schizophr Res. 2011 May;128(1-3):150-5. doi: 10.1016/j.schres.2011.01.019. Epub 2011 Feb 18.
• [22] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [23] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.