Fostamatinib disodium

Biological Activity

Fostamatinib disodium (R788, R-935788) is a potent, ATP-competitive and selective Syk (Spleen tyrosine kinase) inhibitor with IC50 of 41 nM. It is an orally available disodium salt of the Syk kinase inhibitor fostamatinib with potential anti-inflammatory and immunomodulating activities. Syk kinase, widely expressed in hematopoietic cells, is a nonreceptor tyrosine kinase that is involved in coupling activated immunoreceptors to signal downstream events that mediate diverse cellular responses, including proliferation, differentiation, and phagocytosis. Fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. It effectively inhibits BCR signaling in vivo, resulting in reduced proliferation and survival of the malignant B cells and significantly prolonged survival of the treated animals. The growth-inhibitory effect of Fostamatinib disodium occurs despite the relatively modest cytotoxic effect in vitro and is independent of basal Syk activity, suggesting that Fostamatinib disodium (R788) functions primarily by inhibiting antigen-dependent BCR signals. Importantly, the effect of Fostamatinib disodium was found to be selective for the malignant clones, as no disturbance in the production of normal B lymphocytes was observed.

Chemical Information

Molecular Weight	624.42
Formula	C23H24FN6O9PNa2
CAS Number	1025687-58-4
Solubility (25°C)	DMSO 18 mg/mL (ultrasonic and warming)
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Hoellenriegel et al. Leukemia. Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration.

[2] Leonhardt et al. Leukemia. Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels.

[3] Barr et al. Clin Immunol. Syk inhibition with fostamatinib leads to transitional B lymphocyte depletion.

[4] Hilgendorf et al. Arterioscler Thromb Vasc Biol. The oral spleen tyrosine kinase inhibitor fostamatinib attenuates inflammation and atherogenesis in low-density lipoprotein receptor-deficient mice.