Fostamatinib [[6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl
dihydrogen phosphate] is an oral prodrug that is rapidly converted to a
molecule named Tamatinib (or R406), which is potent and relatively selective
inhibitor of Spleen tyrosine kinase (Syk).
Tamatinib is an ATP-competitive
inhibitor of biochemical Syk activity (Ki = 30 nM). The IC50
for this compound is 41 nM, and it inhibits 78% of Syk activity at a
concentration of 0.3 uM. Tamatinib also inhibits the isolated enzymes Lyn (IC50
= 63 nM) and Lck (IC50 = 37 nM). Tamatinib have potent anti-inflammatory
activity, suggesting a role for Syk inhibition in the treatment of rheumatoid
arthritis [1].
Despite similar IC50 values on
isolated kinases, Tamatinib shows selectivity in cell-based assays. In mast
cells activated by FcεRI-crosslinking, the compound
is 20-fold more potent for inhibition of linker for activation of T cells (LAT)
tyrosine residue Y191 phosphorylation (a Syk kinase substrate; EC50
approximately 0.08 uM) compared with phosphorylation of Syk itself at the Y352
residue (a Lyn substrate; EC50 greater than 2 uM). Moreover,
Tamatinib was identified as a potent inhibitor of FcεRI -dependent mast cell activation (EC50 = 43
nM) in primary human mast cells [1].
Rigel Pharmaceuticals is credited with discovering Tamatinib and Fostamatinib. AstraZeneca announced an exclusive worldwide license agreement with Rigel Pharmaceuticals in February 2010 for the global development and commercialization of Fostamatinib. On June 4, 2013, Astra Zeneca announced they were giving up future development on the compound, and terminated their license with Rigel after early results from a Phase IIb study for Rheumatoid Arthritis.
On Sept 8, 2015 Rigel Pharmaceuticals, Inc. discosed that U.S. Food and Drug Administration (US-FDA) has granted Orphan Drug designation to Fostamatinib, Rigel's oral spleen tyrosine kinase inhibitor which is currently in Phase 3 clinical studies in patients with chronic immune thrombocytopenic purpura or ITP. Rigel's Phase 3 program for Fostamatinib in ITP, called FIT, has surpassed the half-way point in enrollment and Rigel expects the program to read out results in mid-2016.
About ITP
Immune Thrombocytopenic Purpura (ITP) is an autoimmune disease where the immune system attacks and destroys platelets in the blood. This results in abnormally low platelet counts.
There are two forms of ITP:
a: acute thrombocytopenic purpura, which is most commonly seen in young children;
b: chronic thrombocytopenic purpura, which requires continual follow up care with a hematologist.
50,000-60,000 people suffer from chronic ITP-the majority are women. Antibodies, usually of the IgG type, mediate platelet destruction in ITP. Fostamatinib has a novel mechanism of action, blocking IgG receptor signaling in both macrophages and B cells via SYK kinase.
Rigel Pharmaceuticals is credited with discovering Tamatinib and Fostamatinib. AstraZeneca announced an exclusive worldwide license agreement with Rigel Pharmaceuticals in February 2010 for the global development and commercialization of Fostamatinib. On June 4, 2013, Astra Zeneca announced they were giving up future development on the compound, and terminated their license with Rigel after early results from a Phase IIb study for Rheumatoid Arthritis.
On Sept 8, 2015 Rigel Pharmaceuticals, Inc. discosed that U.S. Food and Drug Administration (US-FDA) has granted Orphan Drug designation to Fostamatinib, Rigel's oral spleen tyrosine kinase inhibitor which is currently in Phase 3 clinical studies in patients with chronic immune thrombocytopenic purpura or ITP. Rigel's Phase 3 program for Fostamatinib in ITP, called FIT, has surpassed the half-way point in enrollment and Rigel expects the program to read out results in mid-2016.
About ITP
Immune Thrombocytopenic Purpura (ITP) is an autoimmune disease where the immune system attacks and destroys platelets in the blood. This results in abnormally low platelet counts.
There are two forms of ITP:
a: acute thrombocytopenic purpura, which is most commonly seen in young children;
b: chronic thrombocytopenic purpura, which requires continual follow up care with a hematologist.
50,000-60,000 people suffer from chronic ITP-the majority are women. Antibodies, usually of the IgG type, mediate platelet destruction in ITP. Fostamatinib has a novel mechanism of action, blocking IgG receptor signaling in both macrophages and B cells via SYK kinase.
The activity of Tamatinib is
as follows:
IC50 (SYK enzyme
assay) = 41 nM; Ki = 30 nM
IC50 (LYN enzyme
assay) = 63 nM
IC50 (LCK enzyme assay)
= 37 nM
Common Name: Fostamatinib
Synonyms: R935788;
R 935788; R-935788; R788; R 788, R-788
IUPAC Name: [6-({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-4-yl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl
dihydrogen phosphate
CAS Number: 901119-35-5;
1025687-58-4 (disodium salt)
SMILES:
Mechanism of Action: Kinase
Inhibitor; SYK Inhibitor
Indication: Various
Cancers; Anti-inflammatory Agents; Treatment for Rheumatoid Arthritis
(withdrawn); Treatment for Immune Thrombocytopenic Purpura
Development Stage: Phase
III
Company: Rigel Pharmaceuticals
Common Name: Tamatinib
Synonyms: R406;
R-406; R 406
IUPAC Name: [6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one
CAS Number: 841290-80-0
SMILES:
Mechanism of Action: Kinase
Inhibitor; SYK Inhibitor
Indication: Various
Cancers; Anti-inflammatory Agents; Treatment for Rheumatoid Arthritis
(withdrawn); Treatment for Immune Thrombocytopenic Purpura
Development Stage: Phase
III
Company: Rigel Pharmaceuticals
References:
1. Braselmann, S.; et. al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 2006, 319(3), 998-1008.
References:
1. Braselmann, S.; et. al. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther 2006, 319(3), 998-1008.
