Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs

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• 作者：Sang Jae Lee ; Jang‐Sik Choi ; Byeong‐Gu Han ; Hyoun Sook Kim ; Ho‐Juhn Song ; Jaekyoo Lee ; Seungyoon Nam ; Sung‐Ho Goh ; Jung‐Ho Kim ; Jong Sung Koh ; et al
• 刊名：FEBS Journal
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：283
• 期：19
• 页码：3613-3625
• 全文大小：1.2MB
• ISSN：1742-4658

文摘

Spleen tyrosine kinase (SYK) is a cytosolic nonreceptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B-cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Here, we report the crystal structures of SYK in complex with seven newly developed inhibitors (G206, G207, O178, O194, O259, O272, and O282) to provide structural insights into which substituents of the inhibitors and binding regions of SYK are essential for lead compound optimization. Our kinase inhibitors exhibited high inhibitory activities against SYK, with half-maximal inhibitory concentrations (IC₅₀) of approximately 0.7–33 nm, but they showed dissimilar inhibitory activities against KDR, RET, JAK2, JAK3, and FLT3. Among the seven SYK inhibitors, O272 and O282 exhibited highly specific inhibitions against SYK, whereas O194 exhibited strong inhibition of both SYK and FLT3. Three inhibitors (G206, G207, and O178) more efficiently inhibited FLT3 while still substantially inhibiting SYK activity. The binding mode analysis suggested that a highly selective SYK inhibitor can be developed by optimizing the functional groups that facilitate direct interactions with Asn499.