Target Information
| Target General Information | Top | |||||
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| Target ID |
T49493
(Former ID: TTDS00498)
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| Target Name |
Hemoglobin (HB)
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| Synonyms |
Hemoglobin subunit alpha; Hemoglobin alpha chain; HBA1; Alpha-globin
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| Gene Name |
HBA2
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 2 Target-related Diseases | + | ||||
| 1 | Iron deficiency anaemia [ICD-11: 3A00] | |||||
| 2 | Sickle-cell disorder [ICD-11: 3A51] | |||||
| Function |
Involved in oxygen transport from the lung to the various peripheral tissues.
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| BioChemical Class |
Pore-forming globin
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| UniProt ID | ||||||
| Sequence |
MVLSPADKTNVKAAWGKVGAHAGEYGAEALERMFLSFPTTKTYFPHFDLSHGSAQVKGHG
KKVADALTNAVAHVDDMPNALSALSDLHAHKLRVDPVNFKLLSHCLLVTLAAHLPAEFTP AVHASLDKFLASVSTVLTSKYR Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| ADReCS ID | BADD_A06271 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 3 Approved Drugs | + | ||||
| 1 | Iron | Drug Info | Approved | Iron-deficiency anemia | [2] | |
| 2 | Iron Dextran | Drug Info | Approved | Iron-deficiency anemia | [3], [4] | |
| 3 | Voxelotor | Drug Info | Approved | Sickle-cell disorder | [5] | |
| Clinical Trial Drug(s) | [+] 9 Clinical Trial Drugs | + | ||||
| 1 | Efaproxyn | Drug Info | Phase 3 | Lung cancer | [6] | |
| 2 | PolyHeme | Drug Info | Phase 3 | Blood forming organ disorder | [7] | |
| 3 | GBT021601 | Drug Info | Phase 2/3 | Sickle-cell disorder | [8] | |
| 4 | Hemoglobin raffimer | Drug Info | Phase 2/3 | Anemia | [9] | |
| 5 | 5-hydroxymethyl-2-furfural | Drug Info | Phase 2 | Anemia | [10] | |
| 6 | FBS-0701 | Drug Info | Phase 2 | Iron overload disease | [11] | |
| 7 | HQK-1001 | Drug Info | Phase 2 | Beta thalassemia | [12] | |
| 8 | CTX110 | Drug Info | Phase 1/2 | Non-hodgkin lymphoma | [13] | |
| 9 | OXY-111A | Drug Info | Phase 1/2 | Cardiovascular disease | [14] | |
| Discontinued Drug(s) | [+] 9 Discontinued Drugs | + | ||||
| 1 | Hemoximer | Drug Info | Discontinued in Phase 3 | Hypotension | [15] | |
| 2 | VX-366 | Drug Info | Discontinued in Phase 2 | Constitutional neutropenia | [16] | |
| 3 | HRC-302 | Drug Info | Discontinued in Phase 1 | Chronic myelogenous leukaemia | [17] | |
| 4 | AN-10 | Drug Info | Terminated | Alopecia | [18] | |
| 5 | Diaspirin crosslinked hemoglobin | Drug Info | Terminated | Cerebrovascular ischaemia | [19] | |
| 6 | HRC-101 | Drug Info | Terminated | Blood transfusion | [20] | |
| 7 | HRC-102 | Drug Info | Terminated | Reperfusion injury | [21] | |
| 8 | HRC-201 | Drug Info | Terminated | Liver cancer | [22] | |
| 9 | RHb1.1 | Drug Info | Terminated | Anemia | [23] | |
| Mode of Action | [+] 6 Modes of Action | + | ||||
| Activator | [+] 2 Activator drugs | + | ||||
| 1 | Iron | Drug Info | [1] | |||
| 2 | Iron Dextran | Drug Info | [1] | |||
| Modulator | [+] 11 Modulator drugs | + | ||||
| 1 | Voxelotor | Drug Info | [5] | |||
| 2 | PolyHeme | Drug Info | [25] | |||
| 3 | Hemoglobin raffimer | Drug Info | [27] | |||
| 4 | 5-hydroxymethyl-2-furfural | Drug Info | [28] | |||
| 5 | FBS-0701 | Drug Info | [29] | |||
| 6 | HRC-302 | Drug Info | [35] | |||
| 7 | AN-10 | Drug Info | [36] | |||
| 8 | Diaspirin crosslinked hemoglobin | Drug Info | [37] | |||
| 9 | HRC-101 | Drug Info | [38] | |||
| 10 | HRC-102 | Drug Info | [39] | |||
| 11 | RHb1.1 | Drug Info | [40] | |||
| Inhibitor | [+] 10 Inhibitor drugs | + | ||||
| 1 | Efaproxyn | Drug Info | [24] | |||
| 2 | GBT021601 | Drug Info | [26] | |||
| 3 | VX-366 | Drug Info | [34] | |||
| 4 | 1,3,5-BENZENETRICARBOXYLIC ACID | Drug Info | [41] | |||
| 5 | 2,6-DICARBOXYNAPHTHALENE | Drug Info | [41] | |||
| 6 | 2-[(2-methoxy-5-methylphenoxy)methyl]pyridine | Drug Info | [41] | |||
| 7 | 4-Carboxycinnamic Acid | Drug Info | [41] | |||
| 8 | 4-[(5-methoxy-2-methylphenoxy)methyl]pyridine | Drug Info | [41] | |||
| 9 | Heme | Drug Info | [41] | |||
| 10 | SEBACIC ACID | Drug Info | [41] | |||
| Inducer | [+] 1 Inducer drugs | + | ||||
| 1 | HQK-1001 | Drug Info | [30] | |||
| Enhancer | [+] 2 Enhancer drugs | + | ||||
| 1 | OXY-111A | Drug Info | [32] | |||
| 2 | HRC-201 | Drug Info | [39] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | Hemoximer | Drug Info | [33] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Nitric oxide | Ligand Info | |||||
| Structure Description | Crystal Structure of Deoxygenated Hemoglobin in Complex with an Allosteric Effector and Nitric Oxide | PDB:5E29 | ||||
| Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | No | [42] |
| PDB Sequence |
VLSPADKTNV
10 KAAWGKVGAH20 AGEYGAEALE30 RMFLSFPTTK40 TYFPHFDLSH50 GSAQVKGHGK 60 KVADALTNAV70 AHVDDMPNAL80 SALSDLHAHK90 LRVDPVNFKL100 LSHCLLVTLA 110 AHLPAEFTPA120 VHASLDKFLA130 SVSTVLTSKY140 R
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Efaproxyn | Ligand Info | |||||
| Structure Description | HIGH RESOLUTION CRYSTAL STRUCTURE OF DEOXY HEMOGLOBIN COMPLEXED WITH A POTENT ALLOSTERIC EFFECTOR | PDB:1G9V | ||||
| Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | No | [43] |
| PDB Sequence |
VLSPADKTNV
10 KAAWGKVGAH20 AGEYGAEALE30 RMFLSFPTTK40 TYFPHFDLSH50 GSAQVKGHGK 60 KVADALTNAV70 AHVDDMPNAL80 SALSDLHAHK90 LRVDPVNFKL100 LSHCLLVTLA 110 AHLPAEFTPA120 VHASLDKFLA130 SVSTVLTSKY140 R
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| Degree | 6 | Degree centrality | 6.45E-04 | Betweenness centrality | 3.33E-05 |
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| Closeness centrality | 1.67E-01 | Radiality | 1.26E+01 | Clustering coefficient | 1.33E-01 |
| Neighborhood connectivity | 4.00E+00 | Topological coefficient | 2.62E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 2 KEGG Pathways | + | ||||
| 1 | African trypanosomiasis | |||||
| 2 | Malaria | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | Erythrocytes take up carbon dioxide and release oxygen | |||||
| 2 | Erythrocytes take up oxygen and release carbon dioxide | |||||
| 3 | Scavenging of heme from plasma | |||||
| WikiPathways | [+] 7 WikiPathways | + | ||||
| 1 | Binding and Uptake of Ligands by Scavenger Receptors | |||||
| 2 | Uptake of Carbon Dioxide and Release of Oxygen by Erythrocytes | |||||
| 3 | Uptake of Oxygen and Release of Carbon Dioxide by Erythrocytes | |||||
| 4 | Factors involved in megakaryocyte development and platelet production | |||||
| 5 | Folate Metabolism | |||||
| 6 | Vitamin B12 Metabolism | |||||
| 7 | Selenium Micronutrient Network | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Efficacy and safety of total dose infusion of low molecular weight iron dextran in the treatment of iron deficiency anemia during pregnancy. J Coll Physicians Surg Pak. 2008 Jul;18(7):424-7. | |||||
| REF 2 | Drug information of Iron, 2008. eduDrugs. | |||||
| REF 3 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 010787. | |||||
| REF 4 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 5 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019 | |||||
| REF 6 | ClinicalTrials.gov (NCT00083304) Whole Brain Radiation Therapy With Oxygen, With or Without RSR13, in Women With Brain Metastases From Breast Cancer. U.S. National Institutes of Health. | |||||
| REF 7 | ClinicalTrials.gov (NCT00076648) Safety and Efficacy of PolyHeme(R) in Hemorrhagic Shock Following Traumatic Injuries Beginning in the Pre-Hospital Setting. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT05632354) An Open-label Extension Study to Evaluate the Long-term Safety of GBT021601 Administered to Participants With Sickle Cell Disease Who Have Participated in a GBT021601 Clinical Trial. U.S.National Institutes of Health. | |||||
| REF 9 | ClinicalTrials.gov (NCT00038454) Phase II Study To Evaluate The Safety and Efficacy of Hemoglobin Raffimer in Patients Undergoing First Time CABG Surgery. U.S. National Institutes of Health. | |||||
| REF 10 | ClinicalTrials.gov (NCT01987908) Evaluation of Different Dose Regimens of Aes-103 Given for 28 Days to Subjects With Stable Sickle Cell Disease. U.S. National Institutes of Health. | |||||
| REF 11 | ClinicalTrials.gov (NCT01186419) Safety and Pharmacodynamic Study of an Oral Iron Chelator Given for 6 Months to Patients With Iron Overload. U.S. National Institutes of Health. | |||||
| REF 12 | A phase 2 trial of HQK-1001 in HbE-beta thalassemia demonstrates HbF induction and reduced anemia. Blood. 2014 Mar 20;123(12):1956-7. | |||||
| REF 13 | ClinicalTrials.gov (NCT04035434) A Safety and Efficacy Study Evaluating CTX110 in Subjects With Relapsed or Refractory B-Cell Malignancies (CARBON). U.S. National Institutes of Health. | |||||
| REF 14 | ClinicalTrials.gov (NCT02528526) Effects of OXY111A in Primary and Secondary Hepato-Pancreato-Biliary Neoplasm. | |||||
| REF 15 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008774) | |||||
| REF 16 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006007) | |||||
| REF 17 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014790) | |||||
| REF 18 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008114) | |||||
| REF 19 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005412) | |||||
| REF 20 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016356) | |||||
| REF 21 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016740) | |||||
| REF 22 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020214) | |||||
| REF 23 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008362) | |||||
| REF 24 | Increased oxygenation of intracranial tumors by efaproxyn (efaproxiral), an allosteric hemoglobin modifier: In vivo EPR oximetry study. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1503-9. | |||||
| REF 25 | Blood substitutes- the polyheme trials. Mcgill J Med. 2008 January; 11(1): 59-65. | |||||
| REF 26 | GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model. Br J Haematol. 2023 Jul;202(1):173-183. | |||||
| REF 27 | Use of hemoglobin raffimer for postoperative life-threatening anemia in a Jehovah's Witness. Can J Anaesth. 2005 Apr;52(4):369-73. | |||||
| REF 28 | 5-hydroxymethyl-2-furfural modifies intracellular sickle haemoglobin and inhibits sickling of red blood cells. Br J Haematol. 2005 Feb;128(4):552-61. | |||||
| REF 29 | A high-affinity fully human anti-IL-6 mAb, 1339, for the treatment of multiple myeloma. Clin Cancer Res. 2009 Dec 1;15(23):7144-52. | |||||
| REF 30 | A phase 2 study of HQK-1001, an oral fetal haemoglobin inducer, in beta-thalassaemia intermedia. Br J Haematol. 2014 Feb;164(3):456-8. | |||||
| REF 31 | Clinical pipeline report, company report or official report of CRISPR Therapeutics. | |||||
| REF 32 | Modulating the oxygen affinity of human fetal haemoglobin with synthetic allosteric modulators. Br J Haematol. 1998 Sep;102(5):1165-71. | |||||
| REF 33 | Effect of NaBH4 Concentration and Reaction Time on Physical Properties of Glutaraldehyde-Polymerized Hemoglobin. Biotechnology Progress. 05/2004; 20(3):946-52. | |||||
| REF 34 | A combination of hydroxyurea and isobutyramide to induce fetal hemoglobin in transgenic mice is more hematotoxic than the individual agents. Blood Cells Mol Dis. 1999 Jun-Aug;25(3-4):255-69. | |||||
| REF 35 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014790) | |||||
| REF 36 | Genes for Development, Cell Growth and Infectious Diseases, Gabriel Gachelin, 1995. Page(215). | |||||
| REF 37 | Diaspirin cross-linked hemoglobin infusion did not influence base deficit and lactic acid levels in two clinical trials of traumatic hemorrhagic shock patient resuscitation. J Trauma. 2010 May;68(5):1158-71. | |||||
| REF 38 | The novel hemoglobin-based oxygen carrier HRC 101 improves survival in murine sickle cell disease. Anesthesiology. 2007 Aug;107(2):281-7. | |||||
| REF 39 | WO patent application no. 2013,1850,32, Nanotherapeutics for drug targeting. | |||||
| REF 40 | Effects of recombinant-hemoglobin solutions rHb2.0 and rHb1.1 on blood pressure, intestinal blood flow, and gut oxygenation in a rat model of hemorrhagic shock. J Lab Clin Med. 2005 Jan;145(1):21-32. | |||||
| REF 41 | The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. | |||||
| REF 42 | Design, Synthesis, and Investigation of Novel Nitric Oxide (NO)-Releasing Prodrugs as Drug Candidates for the Treatment of Ischemic Disorders: Insights into NO-Releasing Prodrug Biotransformation and Hemoglobin-NO Biochemistry. Biochemistry. 2015 Dec 15;54(49):7178-92. | |||||
| REF 43 | High-resolution crystal structure of deoxy hemoglobin complexed with a potent allosteric effector. Protein Sci. 2001 May;10(5):951-7. | |||||
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