Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRQG4WA)

• DOT Name: Hemoglobin subunit delta (HBD)
• Synonyms: Delta-globin; Hemoglobin delta chain
• Gene Name: HBD
• Related Disease:
  Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
  Sickle-cell anaemia
  Acute erythroid leukemia
  Advanced cancer
  Alpha thalassemia
  Beta thalassemia
  Beta thalassemia
  Colon cancer
  Colon carcinoma
  Hemoglobinopathy
  Keloid
  Melorheostosis
  Multiple sclerosis
  Mycosis fungoides
  Neoplasm
  Nervous system inflammation
  Refractory chronic myeloid leukaemia
  Thalassemia
  Thalassemia
  Hemoglobin E disease
  Delta-beta-thalassemia
  Beta-thalassemia intermedia
  Brain neoplasm
  Iron-deficiency anemia
• UniProt ID: HBD_HUMAN
• PDB ID: 1SHR; 1SI4
• Pfam ID: PF00042
• Sequence:
  MVHLTPEEKTAVNALWGKVNVDAVGGEALGRLLVVYPWTQRFFESFGDLSSPDAVMGNPK
  VKAHGKKVLGAFSDGLAHLDNLKGTFSQLSELHCDKLHVDPENFRLLGNVLVCVLARNFG
  KEFTPQMQAAYQKVVAGVANALAHKYH
• Function: Involved in oxygen transport from the lung to the various peripheral tissues.
• Tissue Specificity: Red blood cells.
• Reactome Pathway: Factors involved in megakaryocyte development and platelet production (R-HSA-983231)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome	DISD21FA	Definitive	Biomarker	[1]
Sickle-cell anaemia	DIS5YNZB	Definitive	Altered Expression	[2]
Acute erythroid leukemia	DISZFC1O	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alpha thalassemia	DIS5XGK0	Strong	Biomarker	[5]
Beta thalassemia	DIS5RCQK	Strong	Genetic Variation	[6]
Beta thalassemia	DIS5RCQK	Strong	Genetic Variation	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[8]
Hemoglobinopathy	DISCT4GX	Strong	Genetic Variation	[9]
Keloid	DISV09JY	Strong	Biomarker	[10]
Melorheostosis	DISIMCL3	Strong	Genetic Variation	[11]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[12]
Mycosis fungoides	DIS62RB8	Strong	Altered Expression	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Nervous system inflammation	DISB3X5A	Strong	Altered Expression	[12]
Refractory chronic myeloid leukaemia	DIS40YPP	Strong	Genetic Variation	[15]
Thalassemia	DIS76XZB	Strong	Genetic Variation	[16]
Thalassemia	DIS76XZB	Strong	Genetic Variation	[7]
Hemoglobin E disease	DIS5OW63	moderate	Genetic Variation	[17]
Delta-beta-thalassemia	DIS6CWYR	Supportive	Autosomal recessive	[18]
Beta-thalassemia intermedia	DISYQ0NL	Limited	Biomarker	[19]
Brain neoplasm	DISY3EKS	Limited	Genetic Variation	[20]
Iron-deficiency anemia	DIS0VQYF	Limited	Genetic Variation	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Hemoglobin subunit delta (HBD).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Hemoglobin subunit delta (HBD).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Hemoglobin subunit delta (HBD).	[24]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Hemoglobin subunit delta (HBD).	[25]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Hemoglobin subunit delta (HBD).	[26]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Hemoglobin subunit delta (HBD).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hemoglobin subunit delta (HBD).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Hemoglobin subunit delta (HBD).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Hemoglobin subunit delta (HBD).	[26]

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 Hemoglobin subunit delta (HBD).	[28]

References

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• [2] Activation of delta-globin gene expression by erythroid Krupple-like factor: a potential approach for gene therapy of sickle cell disease.Blood. 1996 Nov 15;88(10):4051-7.
• [3] Spontaneous delta- to beta-globin switching in K562 human leukemia cells.Blood. 1992 Feb 1;79(3):820-5.
• [4] Pattern of mRNA expression of beta-defensins in basal cell carcinoma.BMC Cancer. 2006 Jun 23;6:163. doi: 10.1186/1471-2407-6-163.
• [5] Crystal structures of HbA2 and HbE and modeling of hemoglobin delta 4: interpretation of the thermal stability and the antisickling effect of HbA2 and identification of the ferrocyanide binding site in Hb.Biochemistry. 2004 Oct 5;43(39):12477-88. doi: 10.1021/bi048903i.
• [6] Genetic basis of persistent red blood cell microcytosis in the Chinese unexplained by phenotypical testing.J Clin Pathol. 2015 Jan;68(1):69-72. doi: 10.1136/jclinpath-2014-202568. Epub 2014 Oct 28.
• [7] Borderline hemoglobin A(2) levels in northern Thai population: HBB genotypes and effects of coinherited alpha-thalassemia.Blood Cells Mol Dis. 2019 Feb;74:13-17. doi: 10.1016/j.bcmd.2018.10.002. Epub 2018 Oct 4.
• [8] Expression and new exon mutations of the human Beta defensins and their association on colon cancer development.PLoS One. 2015 Jun 3;10(6):e0126868. doi: 10.1371/journal.pone.0126868. eCollection 2015.
• [9] Delta globin gene variations leading to reduction in HbA(2) levels.Int J Lab Hematol. 2016 Dec;38(6):610-615. doi: 10.1111/ijlh.12548. Epub 2016 Jul 27.
• [10] Comparative proteomic analysis between normal skin and keloid scar.Br J Dermatol. 2010 Jun;162(6):1302-15. doi: 10.1111/j.1365-2133.2010.09660.x. Epub 2010 Feb 1.
• [11] Evidence for a globin promoter-specific silencer element located upstream of the human delta-globin gene.Biochem Biophys Res Commun. 1994 Oct 14;204(1):413-8. doi: 10.1006/bbrc.1994.2474.
• [12] Neuregulin1 modulation of experimental autoimmune encephalomyelitis (EAE).J Neuroimmunol. 2018 May 15;318:56-64. doi: 10.1016/j.jneuroim.2018.02.008. Epub 2018 Mar 11.
• [13] Expression of human beta-defensins in patients with mycosis fungoides.Arch Dermatol Res. 2007 Jul;299(4):221-4. doi: 10.1007/s00403-007-0749-6. Epub 2007 Apr 6.
• [14] Structure optimisation to improve the delivery efficiency and cell selectivity of a tumour-targeting cell-penetrating peptide.J Drug Target. 2018 Nov;26(9):777-792. doi: 10.1080/1061186X.2018.1424858. Epub 2018 Jan 16.
• [15] Elevated haemoglobin F in juvenile and adult chronic myelogenous leukaemia.Acta Haematol. 1988;80(1):28-33. doi: 10.1159/000205594.
• [16] Analysis of deletional hereditary persistence of fetal hemoglobin/-thalassemia and -globin gene mutations in Southerwestern China.Mol Genet Genomic Med. 2019 Jun;7(6):e706. doi: 10.1002/mgg3.706. Epub 2019 May 1.
• [17] A genome-wide association identified the common genetic variants influence disease severity in beta0-thalassemia/hemoglobin E.Hum Genet. 2010 Mar;127(3):303-14. doi: 10.1007/s00439-009-0770-2.
• [18] A novel delta-thalassemia mutation A G-->C substitution at codon 30 of the delta-globin gene in a person of southern Italian origin. Hum Mutat. 1992;1(2):169-71. doi: 10.1002/humu.1380010215.
• [19] In vivo activation of the human -globin gene: the therapeutic potential in -thalassemic mice.Haematologica. 2014 Jan;99(1):76-84. doi: 10.3324/haematol.2012.082768. Epub 2013 Jul 19.
• [20] Hemoglobins, Hemorphins, and 11p15.5 Chromosomal Region in Cancer Biology and mmunity with Special Emphasis for Brain Tumors.J Neurol Surg A Cent Eur Neurosurg. 2016 May;77(3):247-57. doi: 10.1055/s-0035-1566120. Epub 2016 Mar 2.
• [21] First report of the spectrum of -globin gene mutations in Omani subjects - identification of novel mutations.Int J Lab Hematol. 2015 Apr;37(2):238-43. doi: 10.1111/ijlh.12272. Epub 2014 Jul 9.
• [22] 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.
• [23] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [24] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [25] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [28] 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.
• [29] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [30] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.