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Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs
Author(s) -
Lee Sang Jae,
Choi JangSik,
Han ByeongGu,
Kim Hyoun Sook,
Song HoJuhn,
Lee Jaekyoo,
Nam Seungyoon,
Goh SungHo,
Kim JungHo,
Koh Jong Sung,
Lee Byung Il
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13831
Subject(s) - syk , tyrosine kinase , cancer research , signal transduction , chemistry , tyrosine kinase inhibitor , kinase , pharmacology , biochemistry , microbiology and biotechnology , biology , medicine , cancer
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 ( IC 50 ) of approximately 0.7–33 n m , but they showed dissimilar inhibitory activities against KDR , RET , JAK 2, JAK 3, and FLT 3. Among the seven SYK inhibitors, O272 and O282 exhibited highly specific inhibitions against SYK , whereas O194 exhibited strong inhibition of both SYK and FLT 3. Three inhibitors (G206, G207, and O178) more efficiently inhibited FLT 3 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. Database The atomic coordinates and structure factors for human SYK are in the Protein Data Bank under accession codes 4XG2 (inhibitor‐free form), 4XG3 (G206), 4XG4 (G207), 5GHV (O178), 4XG6 (O194), 4XG7 (O259), 4XG8 (O272), and 4XG9 (O282).