5TR6

Discovery of TAK-659, an Orally Available Investigational Inhibitor of Spleen Tyrosine Kinase (SYK)

Summary for 5TR6

• Entry DOI: 10.2210/pdb5tr6/pdb
• Related: 5TT7
• Descriptor: Tyrosine-protein kinase SYK, 6-{[(1R,2S)-2-aminocyclohexyl]amino}-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: inhibitor, kinase, leukemia, lymphoma, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane : P43405
• Total number of polymer chains: 1
• Total formula weight: 34104.29

Authors

Yano, J.,Jennings, A.,Lam, B.,Hoffman, I.D. (deposition date: 2016-10-25, release date: 2016-11-30, Last modification date: 2024-03-06)

Primary citation

Lam, B.,Arikawa, Y.,Cramlett, J.,Dong, Q.,de Jong, R.,Feher, V.,Grimshaw, C.E.,Farrell, P.J.,Hoffman, I.D.,Jennings, A.,Jones, B.,Matuszkiewicz, J.,Miura, J.,Miyake, H.,Natala, S.R.,Shi, L.,Takahashi, M.,Taylor, E.,Wyrick, C.,Yano, J.,Zalevsky, J.,Nie, Z.
Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
Bioorg. Med. Chem. Lett., 26:5947-5950, 2016

PubMed Abstract: Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.

PubMed: 27839918
DOI: 10.1016/j.bmcl.2016.10.087

Experimental method

X-RAY DIFFRACTION (1.93 Å)