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http://dx.doi.org/10.14348/molcells.2018.2219

Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors  

Lee, Sang Jae (Research Institute, National Cancer Center)
Choi, Jang-Sik (Oscotec Inc.)
Bong, Seoung Min (Research Institute, National Cancer Center)
Hwang, Hae-Jun (Oscotec Inc.)
Lee, Jaesang (Oscotec Inc.)
Song, Ho-Juhn (Genosco)
Lee, Jaekyoo (Genosco)
Kim, Jung-Ho (Oscotec Inc.)
Koh, Jong Sung (Genosco)
Lee, Byung Il (Research Institute, National Cancer Center)
Publication Information
Molecules and Cells / v.41, no.6, 2018 , pp. 545-552 More about this Journal
Abstract
Spleen tyrosine kinase (SYK) is a cytosolic non-receptor protein tyrosine kinase. Because SYK mediates key receptor signaling pathways involving the B cell receptor and Fc receptors, SYK is an attractive target for autoimmune disease and cancer treatments. To date, representative oral SYK inhibitors, including fostamatinib (R406 or R788), entospletinib (GS-9973), cerdulatinib (PRT062070), and TAK-659, have been assessed in clinical trials. Here, we report the crystal structures of SYK in complex with two newly developed inhibitors possessing 4-aminopyrido[4,3-D]pyrimidine moieties (SKI-G-618 and SKI-O-85). One SYK inhibitor (SKI-G-618) exhibited moderate inhibitory activity against SYK, whereas the other inhibitor (SKI-O-85) exhibited a low inhibitory profile against SYK. Binding mode analysis indicates that a highly potent SYK inhibitor might be developed by modifying and optimizing the functional groups that interact with Leu377, Gly378, and Val385 in the G-loop and the nearby region in SYK. In agreement with our structural analysis, one of our SYK inhibitor (SKI-G-618) shows strong inhibitory activities on the ${\beta}$-hexosaminidase release and phosphorylation of SYK/Vav in RBL-2H3 cells. Taken together, our findings have important implications for the design of high affinity SYK inhibitors.
Keywords
cancer; crystal structure; rheumatoid arthritis; spleen tyrosine kinase; SYK;
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