5Y5U

Crystal structures of spleen tyrosine kinase in complex with a novel inhibitor

Summary for 5Y5U

• Entry DOI: 10.2210/pdb5y5u/pdb
• Descriptor: Tyrosine-protein kinase SYK, 4-[(1-methylindazol-5-yl)amino]-2-(4-oxidanylpiperidin-1-yl)-8H-pyrido[4,3-d]pyrimidin-5-one (3 entities in total)
• Functional Keywords: inhibitor, spleen tyrosine kinase, human kinase, drug discovery, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 69215.65

Authors

Lee, S.J.,Lee, B.I. (deposition date: 2017-08-09, release date: 2018-06-27, Last modification date: 2023-11-22)

Primary citation

Lee, S.J.,Choi, J.S.,Bong, S.M.,Hwang, H.J.,Lee, J.,Song, H.J.,Lee, J.,Kim, J.H.,Koh, J.S.,Lee, B.I.
Crystal Structures of Spleen Tyrosine Kinase in Complex with Two Novel 4-Aminopyrido[4,3-d] Pyrimidine Derivative Inhibitors.
Mol. Cells, 41:545-552, 2018

PubMed 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 -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.

PubMed: 29890824
DOI: 10.14348/molcells.2018.2219

Experimental method

X-RAY DIFFRACTION (2.14 Å)