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

• Published in: The FEBS journal 2016-10, Vol.283 (19), p.3613-3625
• Main Authors: Lee, Sang Jae, Choi, Jang‐Sik, Han, Byeong‐Gu, Kim, Hyoun Sook, Song, Ho‐Juhn, Lee, Jaekyoo, Nam, Seungyoon, Goh, Sung‐Ho, Kim, Jung‐Ho, Koh, Jong Sung, Lee, Byung Il
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer therapies; Crystal structure; Crystallography, X-Ray; Drug Design; drug discovery; Indazoles - chemistry; kinase; Kinases; Models, Molecular; Oxazines - chemistry; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrazines - chemistry; Pyridines - chemistry; Signal transduction; Spleen; spleen tyrosine kinase; Syk Kinase - antagonists & inhibitors; Syk Kinase - chemistry
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.13831

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. 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). Spleen tyrosine kinase (SYK) has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Our crystal structures of SYK in complex with seven newly developed inhibitors can provide structural insights into which substituents (a, b, and c) of the inhibitors, and binding regions of SYK are essential for lead compound optimization.