title: Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs.
abstract: 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.
  
  
  
  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).
authors: Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.|The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Korea.
authors: Sang Jae
authors: 0000-0002-5366-2900
authors: SJ
authors: Lee
authors: Oscotec Inc., Seongnam, Gyeonggi, Korea.
authors: Jang-Sik
authors: JS
authors: Choi
authors: Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
authors: Byeong-Gu
authors: BG
authors: Han
authors: Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
authors: Hyoun Sook
authors: HS
authors: Kim
authors: Genosco, Cambridge, MA, USA.
authors: Ho-Juhn
authors: HJ
authors: Song
authors: Genosco, Cambridge, MA, USA.
authors: Jaekyoo
authors: J
authors: Lee
authors: Department of Life Sciences, College of BioNano Technology, Gachon University, Sungnam, Korea.|Department of Genome Medicine and Science, Graduate School of Medicine, Gachon University, Incheon, Korea.
authors: Seungyoon
authors: S
authors: Nam
authors: Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea.
authors: Sung-Ho
authors: SH
authors: Goh
authors: Oscotec Inc., Seongnam, Gyeonggi, Korea.
authors: Jung-Ho
authors: JH
authors: Kim
authors: Genosco, Cambridge, MA, USA. jskob777@genosco.com.
authors: Jong Sung
authors: JS
authors: Koh
authors: Research Institute, National Cancer Center, Goyang, Gyeonggi, Korea. bilee@ncc.re.kr.
authors: Byung Il
authors: BI
authors: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D007191:Indazoles / Q000737:chemistry; D008958:Models, Molecular; D010078:Oxazines / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011719:Pyrazines / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D009025:Morpholines
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D000072377:Syk Kinase; C000589391:6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; D009025:Morpholines; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine
keywords: crystal structure; drug discovery; kinase; spleen tyrosine kinase