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KMID : 0578320180410060545
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Molecules and Cells
2018 Volume.41 No. 6 p.545 ~ p.552
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Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors
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Lee Sang-Jae
Choi Jang-Sik
Bong Seoung-Min
Hwang Hae-Jun
Lee Jae-Sang
Song Ho-Juhn
Lee Jae-Kyoo
Kim Jung-Ho
Koh Jong-Sung
Lee Byung-Il
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Abstract
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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 β 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.
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KEYWORD
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cancer, crystal structure, rheumatoid arthritis, spleen tyrosine kinase, SYK
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