Repositioning Candidate Details
| Candidate ID: | R1428 |
| Source ID: | DB12010 |
| Source Type: | approved; investigational |
| Compound Type: | small molecule |
| Compound Name: | Fostamatinib |
| Synonyms: | Fostamatinib |
| Molecular Formula: | C23H26FN6O9P |
| SMILES: | COC1=CC(NC2=NC=C(F)C(NC3=NC4=C(OC(C)(C)C(=O)N4COP(O)(O)=O)C=C3)=N2)=CC(OC)=C1OC |
| Structure: |
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| DrugBank Description: | Fostamatinib has been investigated for the treatment and basic science of Rheumatoid Arthritis and Immune Thrombocytopenic Purpura (ITP). It was approved on April 17, 2018, under the trade name Tavalisse for use in ITP . Fostamatinib has also been granted orphan drug status by the FDA . Recently, fostamatinib has been identified as a potential therapeutic for controlling acute respiratory distress syndrome (ARDS) in patients with severe COVID-19 through its ability to modulate the SYK kinase. |
| CAS Number: | 901119-35-5 |
| Molecular Weight: | 580.4595 |
| DrugBank Indication: | Fostamatinib is indicated for use in the treatment of chronic immune thrombocytopenia (ITP) in patients who have had insufficient response to previous therapy . |
| DrugBank Pharmacology: | The active metabolite of fostamatinib, R406, inhibits signal transduction by Fcγ receptors involved in the antibody-mediated destruction of platelets by immune cells in chronic ITP . This results in increased platelet counts in this population. R406 produces inhibition of T and B lymphocyte activation by T-cell receptors (TCRs) and B-cell receptors (BCRs) respectively . It can also inhibit signalling via Fcε receptors which could have applications in treating allergic symptoms through prevention of mast cell degranulation . Inhibition of Fc receptor signalling system also affected by R406 suppresses both dendritic cell maturation and antigen presentation and may contribute to the effects of fostamatinib . As a knock-on effect of disabling signal transduction from Fc receptors, TCRs, and BCRs, the production of inflammatory mediators and cytokines like tumour necrosis factor α, leukotriene C4, interleukin-8, and granulocyte-macrophage colony-stimulating factor. Fostamatinib can produce hypertension through off-target effects |
| DrugBank MoA: | The active metabolite of fostamatinib, R406, is an inhibitor of spleen tyrosine kinase (Syk) . It binds reversibly to the ATP binding pocket with high affinity (Ki = 30nM), inhibiting the kinase activity with an IC50 of 41nM. Syk is a cytosolic protein kinase and part of the signalling cascade which occurs with Fc receptors, TCRs, and BCRs . It contains two src homology 2 (SH2) domains separated by a linker domain. These SH2 domains bind to tyrosine residues on the immunoreceptor tyrosine-based activating motif phosphorylated by Lyn, another kinase in the cascade. This motif is located on the cytoplasmic regions of several immune receptors including Fc receptors, TCRs, BCRs, and natural killer cell receptors. The flexibility provided by the linker enables the protein to bind to many receptor types. Inhibition of Syk suppresses downstream signal transduction . While Syk plays a role in some pathways involved in the generation of the oxidative burst by neutrophils or phagocytosis by macrophages, R406 does not have a significant effect on these processes . This is likely due to redundant pathways which do not involve Syk. Similarly Syk does not produce significant effects on platelet activation despite its involvement in glycoprotein IV and integrin based signalling. Activation of antibody-dependent cell-mediated toxicity by natural killer cells is also unaffected despite the involvement of Syk in Fc receptor signalling . R406 binds to the adenosine A3 receptor as an antagonist as well as the adenosine and monoamine uptake transporters as an inhibitor . It has also been found to be an inhibitor of UDP glucuronosyltransferase UGT1A1, phosphodiesterase PDE5, fatty acid amide hydrolase, 5-lipoxygenase, cathepsin L, and cathepsin S . R406 appears to inhibit a wide range of kinases at higher concentrations . It is thought that inhibition of some of these targets may be responsible for the increase in blood pressure seen with fostamatinib. |
| Targets: | Tyrosine-protein kinase SYK inhibitor; Adenosine receptor A3 antagonist; vesicular monoamine transporter 2 (VMAT2) inhibitor; Fatty-acid amide hydrolase 1 inhibitor; Equilibrative nucleoside transporter 1 inhibitor; UDP-glucuronosyltransferase 1-1 inhibitor; cGMP-specific 3',5'-cyclic phosphodiesterase inhibitor; Arachidonate 5-lipoxygenase inhibitor; Cathepsin S inhibitor; Cathepsin L1 inhibitor; Tyrosine-protein kinase ABL1 inhibitor; Calcium-dependent protein kinase 1 inhibitor; Serine/threonine-protein kinase PknB inhibitor; Ribosomal protein S6 kinase alpha-6 inhibitor; Non-receptor tyrosine-protein kinase TYK2 inhibitor; Atypical kinase COQ8A, mitochondrial inhibitor; Tyrosine-protein kinase JAK1 inhibitor; Hepatocyte growth factor receptor inhibitor; Serine/threonine-protein kinase NIM1 inhibitor; Serine/threonine-protein kinase MST4 inhibitor; cAMP-dependent protein kinase catalytic subunit alpha inhibitor; Serine/threonine-protein kinase 24 inhibitor; Serine/threonine-protein kinase 3 inhibitor; Tyrosine-protein kinase Tec inhibitor; Serine/threonine-protein kinase 33 inhibitor; Serine/threonine-protein kinase 35 inhibitor; Serine/threonine-protein kinase 36 inhibitor; Serine/threonine-protein kinase 38 inhibitor; Serine/threonine-protein kinase 38-like inhibitor; STE20/SPS1-related proline-alanine-rich protein kinase inhibitor; Serine/threonine-protein kinase TAO1 inhibitor; Serine/threonine-protein kinase TAO2 inhibitor; Serine/threonine-protein kinase TAO3 inhibitor; Serine/threonine-protein kinase TBK1 inhibitor; Angiopoietin-1 receptor inhibitor; Dual specificity testis-specific protein kinase 1 inhibitor; TGF-beta receptor type-1 inhibitor; TGF-beta receptor type-2 inhibitor; Tyrosine-protein kinase receptor Tie-1 inhibitor; Serine/threonine-protein kinase tousled-like 1 inhibitor; Serine/threonine-protein kinase tousled-like 2 inhibitor; TRAF2 and NCK-interacting protein kinase inhibitor; Non-receptor tyrosine-protein kinase TNK1 inhibitor; Activated CDC42 kinase 1 inhibitor; Serine/threonine-protein kinase TNNI3K inhibitor; Testis-specific serine/threonine-protein kinase 1 inhibitor; Dual specificity protein kinase TTK inhibitor; Tyrosine-protein kinase TXK inhibitor; Tyrosine-protein kinase receptor TYRO3 inhibitor; Serine/threonine-protein kinase ULK1 inhibitor; Serine/threonine-protein kinase ULK2 inhibitor; Serine/threonine-protein kinase ULK3 inhibitor; Wee1-like protein kinase inhibitor; Tyrosine-protein kinase Yes inhibitor; Mitogen-activated protein kinase kinase kinase 19 inhibitor; Mitogen-activated protein kinase kinase kinase MLT inhibitor; Tyrosine-protein kinase ZAP-70 inhibitor; AP2-associated protein kinase 1 inhibitor; Abelson tyrosine-protein kinase 2 inhibitor; Activin receptor type-1 inhibitor; Activin receptor type-1B inhibitor; Atypical kinase COQ8B, mitochondrial inhibitor; ALK tyrosine kinase receptor inhibitor; Ankyrin repeat and protein kinase domain-containing protein 1 inhibitor; Aurora kinase A inhibitor; Aurora kinase B inhibitor; Aurora kinase C inhibitor; Tyrosine-protein kinase receptor UFO inhibitor; Tyrosine-protein kinase Blk inhibitor; BMP-2-inducible protein kinase inhibitor; Bone morphogenetic protein receptor type-1B inhibitor; Bone morphogenetic protein receptor type-2 inhibitor; Cytoplasmic tyrosine-protein kinase BMX inhibitor; Serine/threonine-protein kinase B-raf inhibitor; Tyrosine-protein kinase BTK inhibitor; Calcium/calmodulin-dependent protein kinase type 1 inhibitor; Calcium/calmodulin-dependent protein kinase type 1D inhibitor; Calcium/calmodulin-dependent protein kinase type 1G inhibitor; Calcium/calmodulin-dependent protein kinase type II subunit alpha inhibitor; Calcium/calmodulin-dependent protein kinase type II subunit beta inhibitor; Calcium/calmodulin-dependent protein kinase type II subunit delta inhibitor; Calcium/calmodulin-dependent protein kinase type II subunit gamma inhibitor; Calcium/calmodulin-dependent protein kinase kinase 1 inhibitor; Calcium/calmodulin-dependent protein kinase kinase 2 inhibitor; Peripheral plasma membrane protein CASK inhibitor; Kappa-casein inhibitor; Cyclin-dependent kinase 1 inhibitor; Serine/threonine-protein kinase MRCK gamma inhibitor; Cyclin-dependent kinase 4 inhibitor; Cyclin-dependent kinase-like 1 inhibitor; Cyclin-dependent kinase-like 2 inhibitor; Serine/threonine-protein kinase Chk1 inhibitor; Serine/threonine-protein kinase Chk2 inhibitor; Citron Rho-interacting kinase inhibitor; Dual specificity protein kinase CLK1 inhibitor; Dual specificity protein kinase CLK2 inhibitor; Dual specificity protein kinase CLK3 inhibitor; Dual specificity protein kinase CLK4 inhibitor; Macrophage colony-stimulating factor 1 receptor inhibitor; Tyrosine-protein kinase CSK inhibitor; Casein kinase I isoform alpha inhibitor; Casein kinase II subunit alpha inhibitor; Casein kinase II subunit alpha' inhibitor; Death-associated protein kinase 1 inhibitor; Death-associated protein kinase 2 inhibitor; Death-associated protein kinase 3 inhibitor; Serine/threonine-protein kinase DCLK1 inhibitor; Serine/threonine-protein kinase DCLK2 inhibitor; Serine/threonine-protein kinase DCLK3 inhibitor; Epithelial discoidin domain-containing receptor 1 inhibitor; Discoidin domain-containing receptor 2 inhibitor; Dual specificity tyrosine-phosphorylation-regulated kinase 1A inhibitor; Dual specificity tyrosine-phosphorylation-regulated kinase 1B inhibitor; Epidermal growth factor receptor inhibitor; Eukaryotic translation initiation factor 2-alpha kinase 1 inhibitor; Interferon-induced, double-stranded RNA-activated protein kinase inhibitor; eIF-2-alpha kinase GCN2 inhibitor; Ephrin type-A receptor 1 inhibitor; Ephrin type-A receptor 2 inhibitor; Ephrin type-A receptor 3 inhibitor; Ephrin type-A receptor 4 inhibitor; Ephrin type-A receptor 5 inhibitor; Ephrin type-A receptor 6 inhibitor; Ephrin type-A receptor 7 inhibitor; Ephrin type-A receptor 8 inhibitor; Ephrin type-B receptor 1 inhibitor; Ephrin type-B receptor 2 inhibitor; Ephrin type-B receptor 4 inhibitor; Ephrin type-B receptor 6 inhibitor; Receptor tyrosine-protein kinase erbB-2 inhibitor; Receptor tyrosine-protein kinase erbB-4 inhibitor; Serine/threonine-protein kinase/endoribonuclease IRE1 inhibitor; Tyrosine-protein kinase Fer inhibitor; Tyrosine-protein kinase Fes/Fps inhibitor; Fibroblast growth factor receptor 1 inhibitor; Fibroblast growth factor receptor 2 inhibitor; Fibroblast growth factor receptor 3 inhibitor; Tyrosine-protein kinase Fgr inhibitor; Vascular endothelial growth factor receptor 1 inhibitor; Receptor-type tyrosine-protein kinase FLT3 inhibitor; Vascular endothelial growth factor receptor 3 inhibitor; Serine/threonine-protein kinase mTOR inhibitor; Tyrosine-protein kinase FRK inhibitor; Tyrosine-protein kinase Fyn inhibitor; Cyclin-G-associated kinase inhibitor; Glycogen synthase kinase-3 alpha inhibitor; Glycogen synthase kinase-3 beta inhibitor; Tyrosine-protein kinase HCK inhibitor; Homeodomain-interacting protein kinase 2 inhibitor; Homeodomain-interacting protein kinase 3 inhibitor; Serine/threonine-protein kinase ICK inhibitor; Inhibitor of nuclear factor kappa-B kinase subunit beta inhibitor; Inhibitor of nuclear factor kappa-B kinase subunit epsilon inhibitor; Insulin receptor inhibitor; Insulin receptor-related protein inhibitor; Interleukin-1 receptor-associated kinase 1 inhibitor; Interleukin-1 receptor-associated kinase 3 inhibitor; Interleukin-1 receptor-associated kinase 4 inhibitor; Tyrosine-protein kinase ITK/TSK inhibitor; Tyrosine-protein kinase JAK2 inhibitor; Tyrosine-protein kinase JAK3 inhibitor; Vascular endothelial growth factor receptor 2 inhibitor; Serine/threonine-protein kinase SIK3 inhibitor; Mast/stem cell growth factor receptor Kit inhibitor; Serine/threonine-protein kinase LATS1 inhibitor; Tyrosine-protein kinase Lck inhibitor; LIM domain kinase 1 inhibitor; LIM domain kinase 2 inhibitor; Leucine-rich repeat serine/threonine-protein kinase 2 inhibitor; Leukocyte tyrosine kinase receptor inhibitor; Tyrosine-protein kinase Lyn inhibitor; Dual specificity mitogen-activated protein kinase kinase 2 inhibitor; Dual specificity mitogen-activated protein kinase kinase 3 inhibitor; Dual specificity mitogen-activated protein kinase kinase 5 inhibitor; Dual specificity mitogen-activated protein kinase kinase 6 inhibitor; Mitogen-activated protein kinase kinase kinase 1 inhibitor; Mitogen-activated protein kinase kinase kinase 10 inhibitor; Mitogen-activated protein kinase kinase kinase 11 inhibitor; Mitogen-activated protein kinase kinase kinase 12 inhibitor; Mitogen-activated protein kinase kinase kinase 13 inhibitor; Mitogen-activated protein kinase kinase kinase 15 inhibitor; Mitogen-activated protein kinase kinase kinase 2 inhibitor; Mitogen-activated protein kinase kinase kinase 3 inhibitor; Mitogen-activated protein kinase kinase kinase 4 inhibitor; Mitogen-activated protein kinase kinase kinase 6 inhibitor; Mitogen-activated protein kinase kinase kinase 9 inhibitor; Mitogen-activated protein kinase kinase kinase kinase 1 inhibitor; Mitogen-activated protein kinase kinase kinase kinase 2 inhibitor; Mitogen-activated protein kinase kinase kinase kinase 3 inhibitor; Mitogen-activated protein kinase kinase kinase kinase 4 inhibitor; Mitogen-activated protein kinase kinase kinase kinase 5 inhibitor; Mitogen-activated protein kinase 10 inhibitor; Mitogen-activated protein kinase 13 inhibitor; Mitogen-activated protein kinase 14 inhibitor; Mitogen-activated protein kinase 15 inhibitor; Mitogen-activated protein kinase 4 inhibitor; Mitogen-activated protein kinase 7 inhibitor; Mitogen-activated protein kinase 9 inhibitor; MAP kinase-activated protein kinase 5 inhibitor; Serine/threonine-protein kinase MARK1 inhibitor; Serine/threonine-protein kinase MARK2 inhibitor; MAP/microtubule affinity-regulating kinase 3 inhibitor; MAP/microtubule affinity-regulating kinase 4 inhibitor; CLIP-associating protein 1 inhibitor; Microtubule-associated serine/threonine-protein kinase 1 inhibitor; Megakaryocyte-associated tyrosine-protein kinase inhibitor; Maternal embryonic leucine zipper kinase inhibitor; Tyrosine-protein kinase Mer inhibitor; Misshapen-like kinase 1 inhibitor; MAP kinase-interacting serine/threonine-protein kinase 1 inhibitor; MAP kinase-interacting serine/threonine-protein kinase 2 inhibitor; Macrophage-stimulating protein receptor inhibitor; Muscle, skeletal receptor tyrosine-protein kinase inhibitor; Myosin light chain kinase, smooth muscle inhibitor; Myosin light chain kinase 2, skeletal/cardiac muscle inhibitor; Myosin light chain kinase 3 inhibitor; Myosin light chain kinase family member 4 inhibitor; Myosin-IIIa inhibitor; Serine/threonine-protein kinase Nek1 inhibitor; Serine/threonine-protein kinase Nek11 inhibitor; Serine/threonine-protein kinase Nek2 inhibitor; Serine/threonine-protein kinase Nek3 inhibitor; Serine/threonine-protein kinase Nek4 inhibitor; Serine/threonine-protein kinase Nek5 inhibitor; Serine/threonine-protein kinase Nek9 inhibitor; High affinity nerve growth factor receptor inhibitor; BDNF/NT-3 growth factors receptor inhibitor; NT-3 growth factor receptor inhibitor; NUAK family SNF1-like kinase 1 inhibitor; NUAK family SNF1-like kinase 2 inhibitor; Serine/threonine-protein kinase OSR1 inhibitor; Serine/threonine-protein kinase PAK 1 inhibitor; Serine/threonine-protein kinase PAK 2 inhibitor; Serine/threonine-protein kinase PAK 3 inhibitor; Serine/threonine-protein kinase PAK 4 inhibitor; Serine/threonine-protein kinase PAK 6 inhibitor; Serine/threonine-protein kinase PAK 5 inhibitor; Cyclin-dependent kinase 16 inhibitor; Cyclin-dependent kinase 17 inhibitor; Platelet-derived growth factor receptor alpha inhibitor; Platelet-derived growth factor receptor beta inhibitor; 3-phosphoinositide-dependent protein kinase 1 inhibitor; Cyclin-dependent kinase 15 inhibitor; Phosphorylase b kinase gamma catalytic chain, skeletal muscle/heart isoform inhibitor; Phosphatidylinositol 4-kinase beta inhibitor; Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit beta inhibitor; Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit gamma inhibitor; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform inhibitor; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform inhibitor; Serine/threonine-protein kinase pim-1 inhibitor; Serine/threonine-protein kinase pim-3 inhibitor; Phosphatidylinositol 5-phosphate 4-kinase type-2 beta inhibitor; Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma inhibitor; Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase inhibitor; Serine/threonine-protein kinase N1 inhibitor; Serine/threonine-protein kinase N2 inhibitor; Serine/threonine-protein kinase PLK1 inhibitor; Serine/threonine-protein kinase PLK2 inhibitor; Serine/threonine-protein kinase PLK3 inhibitor; Serine/threonine-protein kinase PLK4 inhibitor; 5'-AMP-activated protein kinase catalytic subunit alpha-1 inhibitor; 5'-AMP-activated protein kinase inhibitor; cAMP-dependent protein kinase catalytic subunit beta inhibitor; Protein kinase C delta type inhibitor; Protein kinase C epsilon type inhibitor; Protein kinase C gamma type (PRKCG) inhibitor; Protein kinase C iota type inhibitor; Protein kinase C theta type inhibitor; Serine/threonine-protein kinase D1 inhibitor; cGMP-dependent protein kinase 2 inhibitor; Serine/threonine-protein kinase PRP4 homolog inhibitor; Focal adhesion kinase 1 inhibitor; Protein-tyrosine kinase 2-beta inhibitor; Protein-tyrosine kinase 6 inhibitor; RAF proto-oncogene serine/threonine-protein kinase inhibitor; Proto-oncogene tyrosine-protein kinase receptor Ret inhibitor; Serine/threonine-protein kinase RIO1 inhibitor; Serine/threonine-protein kinase RIO2 inhibitor; Serine/threonine-protein kinase RIO3 inhibitor; Receptor-interacting serine/threonine-protein kinase 1 inhibitor; Receptor-interacting serine/threonine-protein kinase 2 inhibitor; Receptor-interacting serine/threonine-protein kinase 4 inhibitor; Rho-associated protein kinase 2 inhibitor; Proto-oncogene tyrosine-protein kinase ROS inhibitor; Ribosomal protein S6 kinase alpha-1 inhibitor; Ribosomal protein S6 kinase alpha-3 inhibitor; Serine/threonine-protein kinase SBK1 inhibitor; Uncharacterized serine/threonine-protein kinase SBK3 inhibitor; Serine/threonine-protein kinase Sgk3 inhibitor; Serine/threonine-protein kinase SIK1 inhibitor; Serine/threonine-protein kinase SIK2 inhibitor; STE20-like serine/threonine-protein kinase inhibitor; SNF-related serine/threonine-protein kinase inhibitor; Proto-oncogene tyrosine-protein kinase Src inhibitor; Tyrosine-protein kinase Srms inhibitor; Serine/threonine-protein kinase 10 inhibitor; Serine/threonine-protein kinase 16 inhibitor; Serine/threonine-protein kinase 17A inhibitor; Serine/threonine-protein kinase 17B inhibitor; Serine/threonine-protein kinase 32A inhibitor |
| Inclusion Criteria: | Target associated |
| Strategy ID | Strategy | Synonyms | Related Targets | Related Drugs | |
|---|---|---|---|---|---|
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I01 | 552 | Pneumonia | A lung disease that involves lung parenchyma or alveolar inflammation and abnormal alveolar filling with fluid (consolidation and exudation). It results from a variety of causes including infection with bacteria, viruses, fungi or parasites, and chemical or physical injury to the lungs. It is accompanied by fever, chills, cough, and difficulty in breathing. http://en.wikipedia.org/wiki/Pneumonia | disease of anatomical entity/respiratory system disease/ lower respiratory tract disease/lung disease | Details |
| I12 | 10763 | Hypertension | An artery disease characterized by chronic elevated blood pressure in the arteries. https://en.wikipedia.org/wiki/Hypertension, https://www.ncbi.nlm.nih.gov/pubmed/24352797 | disease of anatomical entity/ cardiovascular system disease/vascular disease/ artery disease | Details |
| I15 | 1290 | Bone disease | A connective tissue disease that affects the structure or development of bone or causes an impairment of normal bone function. http://en.wikipedia.org/wiki/Bone_disease | disease of anatomical entity/ musculoskeletal system disease/connective tissue disease | Details |