One signaling pathway through which neurons and microglia communicate is the neuronal cytokine CX3CL1 (fractalkine) and its microglial receptor (CX3CR1). CX3CL1 is expressed by neurons either as a membrane-bound or a secreted ligand. The binding of CX3CL1 to CX3CR1 maintains microglia in an “off” state, thereby inhibiting the release of pro-inflammatory cytokines. In contrast, deficiency of CX3CL1 or CX3CR1 leads to an increased production of pro-inflammatory molecules[1]. JMS-17-2 is a potent and selective CX3CR1 antagonist with an IC50 value of 0.32 nM. The favorable potency shown by JMS-17-2 is combined with significant selectivity for CX3CR1 over other chemokine receptors, such as CXCR2 and CXCR1[2]. Interestingly, the two concentrations of JMS-17-2 most effective in blocking FKN-induced ERK phosphorylation also significantly reduced the migration of breast cancer cells in vitro[2]. Pharmacokinetic evaluation of JMS-17-2 administered to mice at a dose of 10 mg/kg (i.p.) produced drug levels of 89 ng/mL (210 nM) in blood measured one hour after dosing, which corresponds to a 20-fold increase over the lowest fully effective dose of this compound in vitro[2]. JMS-17-2 (10 mg/kg; administered i.p.; twice a day for three weeks) caused a dramatic reduction of tumors in both skeleton and visceral organs in SCID mice with MDA-231 xenograft[2].
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