Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors
Sang Jae Lee1,2,5, Jang-Sik Choi3,5, Seoung Min Bong1, Hae-Jun Hwang3, Jaesang Lee3, Ho-Juhn Song4,
Jaekyoo Lee4, Jung-Ho Kim3, Jong Sung Koh4,*, and Byung Il Lee1,*
1Research Institute, National Cancer Center, Goyang, Gyeonggi 10408, Korea, 2The Research Institute of Pharmaceutical Sciences,
College of Pharmacy, Seoul National University, Seoul 08826, Korea, 3Oscotec Inc., Seongnam 13488, Korea, 4Genosco,
767C Concord Ave, 2nd Floor, Cambridge, MA 02138, USA, 5These authors contributed equally to this work.
*Correspondence: (JSK); (BIL)
Received September 15, 2017; Revised March 1, 2018; Accepted April 6, 2018.; Published online June 12, 2018.
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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
Keywords: cancer, crystal structure, rheumatoid arthritis, spleen tyrosine kinase; SYK

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31 May 2018 Volume 41,
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