Given this persis tent unmet need and the promise of multipathway

Given this persis tent unmet need and the promise of multipathway inhi bition to deliver breakthrough efficacy, pharmacological modulation of intracellular signaling components with small molecule agents offers an attractive selleck screening library alternative therapeutic strategy, provided the risk benefit profile is acceptable. In this regard, the SYK BTK Inhibitors,Modulators,Libraries axis is an attrac tive target Inhibitors,Modulators,Libraries because it is critical for antigen receptor signa ling, abnormal regulation of which has been implicated in the pathogenesis of several autoimmune diseases, inclu ding RA and SLE. Among the reported agents targeting the SYK, the in hibitor fostamatinib has demonstrated reduced clinical efficacy compared with other therapeutic agents.

In our hands, however, R788 is not a very selective kinase inhibitor, inhibiting one half of the kinome in the KinaseScan assay, including JAK and vascular endothelial growth factor receptor, which is con sistent Inhibitors,Modulators,Libraries with previous reports, suggesting that the clinical activities of R788 are not solely attributed to SYK inhibition. Some of the off target activities might also account for the observed adverse effects in clinical trials, including high blood pressure, which is due to vascular endothelial growth factor receptor inhibition. R788 is also a relatively weak SYK inhibitor in whole blood assays, which is potentially attributed to high plasma protein binding. A more selective, potent SYK inhibitor will thus be necessary to address the mechanism of action and evaluate the efficacy as well as any potential on mechanism toxicity associated with SYK inhibition in clinical trials.

To this end, we have developed an alternative chemical scaffold of SYK inhibitor, designated RO9021. The protein kinase selectivity profile of RO9021 was assessed Inhibitors,Modulators,Libraries by the widely accepted KinomeScan method, which utilizes a proprietary active site directed competition binding assay to quantitatively measure interactions between test compounds and more than 450 human kinases and disease relevant mutant variants. As shown in Figure 1 and Additional file 1, Figure S1, beside SYK with 99% competi tion only six protein kinases, Inhibitors,Modulators,Libraries including JAK1 and JAK3, have more than 90% competition, indicating that RO9021 has superb selectivity. Since truncated forms of recombin ant JAK1 and JAK3 were utilized in the KinomeScan assay, we examined the ability of RO9021 to inhibit JAK mediated signaling in cell based assays and found the compound had weak or no activity.

In contrast, RO9021 inhibited phosphorylation of SYK downstream effectors, namely PLC2 and Nilotinib purchase BTK, in response to BCR engagement, consistent with the known biology of SYK in BCR signaling. Taken together, these data strongly indicate that the compound effect in cells is mediated by SYK inhib ition. Furthermore, RO9021 has reasonable oral bioavail ability profiles and thus can be used to interrogate the various reported biological roles of SYK in preclinical dis ease models.

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