Binding Mode
As shown in the co-crystal structure of
tamatinib-SYK (Fig. 1), the aminopyrimidine moiety
forms two hydrogen bonds with Ala451 of the hinge
region. In addition, there is an atypical hydrogen bond (CH...O=C) between CH at 6 and amide
carbonyl of Glu449 (Fig. 2).
Uses
Fostamatinib can be used to treat cancers that have acquired resistance to kinase inhibitors.
Indications
Fostamatinib is an FDA-approved first-in-class spleen tyrosine kinase (SYK) inhibitor, specifically indicated for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have not responded adequately to prior therapies.
General Description
Class: non-receptor tyrosine kinase;
Treatment: ITP;
Other name: R788;
Oral bioavailability = 100% (prodrug);
Elimination half-life = 15 h (tamatinib);
Protein binding = 98.3%
Biological Activity
fostamatinib is a small molecule inhibitor of spleen tyrosine kinase (syk) with ic50 value of 41nm [1].fostamatinib is an orally bioavailable prodrug of r406. it is developed for the treatment of autoimmune diseases. the effective metabolite of fostamatinib, r406, is an atp-competitive inhibitor of syk with ki value of 30nm. r406 also inhibits the activity of other kinases including flt3, lyn (ic50=63nm) and lck (ic50=37nm). it is found that r406 inhibits both bcr and fcr mediated responses in vitro. besides that, r406 also shows effects in other cells types and signalling pathways. in the in vivo assay, fostamatinib shows to be highly active to inhibit fcr-mediated signaling in various animal models of allergy, autoimmunity and inflammation. moreover, fostamatinib also exerts efficacy in sle animal models. treatment of fostamatinib suppresses the established renal and skin disease and reduces lymphadenopathy in the mrl/lpr strain [1].
target
Primary target: SYK
References
[1] mcadoo s p, tam f w k. fostamatinib disodium. drugs of the future, 2011, 36(4): 273.
