Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS1SAWM)

• DOT Name: Homeobox protein Nkx-2.5 (NKX2-5)
• Synonyms: Cardiac-specific homeobox; Homeobox protein CSX; Homeobox protein NK-2 homolog E
• Gene Name: NKX2-5
• Related Disease:
  Aortic valve disease 1
  Aortic valve disorder
  Atrial septal defect 7
  Cardiomyopathy
  Congenital hypothyroidism
  Conotruncal heart malformations
  Hypothyroidism, congenital, nongoitrous, 5
  NKX2.5-related congenital, conduction and myopathic heart disease
  Tetralogy of fallot
  Arrhythmia
  Arteriosclerosis
  Atherosclerosis
  Autism spectrum disorder
  Cardiac disease
  Cardiovascular disease
  Dilated cardiomyopathy 1A
  Ebstein anomaly
  High blood pressure
  Myocardial infarction
  Myotonic dystrophy
  Neoplasm
  Patent ductus arteriosus
  Progressive familial heart block, type 1A
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Stroke
  Systemic sclerosis
  T-cell acute lymphoblastic leukaemia
  Hypoplastic left heart syndrome 1
  Athyreosis
  Familial atrial fibrillation
  Familial bicuspid aortic valve
  Familial isolated congenital asplenia
  Hypoplastic left heart syndrome
  Atrial septal defect
  Atrioventricular block
  Dilated cardiomyopathy
  Myotonic dystrophy type 1
  Myotonic dystrophy type 2
  Ventricular septal defect
• UniProt ID: NKX25_HUMAN
• PDB ID: 3RKQ; 4S0H; 6WC2; 6WC5
• Pfam ID: PF00046
• Sequence:
  MFPSPALTPTPFSVKDILNLEQQQRSLAAAGELSARLEATLAPSSCMLAAFKPEAYAGPE
  AAAPGLPELRAELGRAPSPAKCASAFPAAPAFYPRAYSDPDPAKDPRAEKKELCALQKAV
  ELEKTEADNAERPRARRRRKPRVLFSQAQVYELERRFKQQRYLSAPERDQLASVLKLTST
  QVKIWFQNRRYKCKRQRQDQTLELVGLPPPPPPPARRIAVPVLVRDGKPCLGDSAPYAPA
  YGVGLNPYGYNAYPAYPGYGGAACSPGYSCTAAYPAGPSPAQPATAAANNNFVNFGVGDL
  NAVQSPGIPQSNSGVSTLHGIRAW
• Function: Transcription factor required for the development of the heart and the spleen. During heart development, acts as a transcriptional activator of NPPA/ANF in cooperation with GATA4. May cooperate with TBX2 to negatively modulate expression of NPPA/ANF in the atrioventricular canal. Binds to the core DNA motif of NPPA promoter. Together with PBX1, required for spleen development through a mechanism that involves CDKN2B repression. Positively regulates transcription of genes such as COL3A1 and MMP2, resulting in increased pulmonary endothelial fibrosis in response to hypoxia.
• Tissue Specificity: Expressed only in the heart.
• Reactome Pathway:
  Physiological factors (R-HSA-5578768)
  Cardiogenesis (R-HSA-9733709)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aortic valve disease 1	DIS3JI56	Definitive	GermlineCausalMutation	[1]
Aortic valve disorder	DISKLYD7	Definitive	GermlineCausalMutation	[1]
Atrial septal defect 7	DISXT6WF	Definitive	Autosomal dominant	[2]
Cardiomyopathy	DISUPZRG	Definitive	Genetic Variation	[3]
Congenital hypothyroidism	DISL5XVU	Definitive	Biomarker	[4]
Conotruncal heart malformations	DIS7FMIG	Definitive	Semidominant	[5]
Hypothyroidism, congenital, nongoitrous, 5	DIS1X6NZ	Definitive	Autosomal dominant	[6]
NKX2.5-related congenital, conduction and myopathic heart disease	DISZ25DZ	Definitive	Autosomal dominant	[7]
Tetralogy of fallot	DISMHFNW	Definitive	Autosomal dominant	[8]
Arrhythmia	DISFF2NI	Strong	Genetic Variation	[9]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[10]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[10]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[11]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[12]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[13]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Biomarker	[14]
Ebstein anomaly	DISO3NHV	Strong	Genetic Variation	[15]
High blood pressure	DISY2OHH	Strong	Biomarker	[13]
Myocardial infarction	DIS655KI	Strong	Biomarker	[16]
Myotonic dystrophy	DISNBEMX	Strong	Altered Expression	[17]
Neoplasm	DISZKGEW	Strong	Altered Expression	[18]
Patent ductus arteriosus	DIS9P8YS	Strong	Genetic Variation	[19]
Progressive familial heart block, type 1A	DISUPY6A	Strong	GermlineModifyingMutation	[20]
Prostate cancer	DISF190Y	Strong	Altered Expression	[21]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[21]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[22]
Stroke	DISX6UHX	Strong	Biomarker	[23]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[13]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[24]
Hypoplastic left heart syndrome 1	DISW3OY8	moderate	Biomarker	[25]
Athyreosis	DISBHHCU	Supportive	Autosomal dominant	[6]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[26]
Familial bicuspid aortic valve	DISL0BRK	Supportive	Autosomal dominant	[1]
Familial isolated congenital asplenia	DIS60HWJ	Supportive	Autosomal dominant	[27]
Hypoplastic left heart syndrome	DISSLFZ4	Disputed	Biomarker	[28]
Atrial septal defect	DISJT76B	Limited	Genetic Variation	[29]
Atrioventricular block	DIS8YLE6	Limited	Genetic Variation	[30]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[7]
Myotonic dystrophy type 1	DISJC0OX	Limited	Altered Expression	[31]
Myotonic dystrophy type 2	DIS5ZWF1	Limited	Biomarker	[17]
Ventricular septal defect	DISICO41	Limited	Biomarker	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homeobox protein Nkx-2.5 (NKX2-5).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Homeobox protein Nkx-2.5 (NKX2-5).	[34]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Homeobox protein Nkx-2.5 (NKX2-5).	[35]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Homeobox protein Nkx-2.5 (NKX2-5).	[36]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Homeobox protein Nkx-2.5 (NKX2-5).	[37]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeobox protein Nkx-2.5 (NKX2-5).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Homeobox protein Nkx-2.5 (NKX2-5).	[40]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Homeobox protein Nkx-2.5 (NKX2-5).	[41]

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 Homeobox protein Nkx-2.5 (NKX2-5).	[38]

References

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• [23] Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.Nat Genet. 2018 Apr;50(4):524-537. doi: 10.1038/s41588-018-0058-3. Epub 2018 Mar 12.
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