Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK). Issue 24 (15th December 2016)

• Record Type: Journal Article
• Authors: Lam, Betty; Arikawa, Yasuyoshi; Cramlett, Joshua; Dong, Qing; de Jong, Ron; Feher, Victoria; Grimshaw, Charles E.; Farrell, Pamela J.; Hoffman, Isaac D.; Jennings, Andy; Jones, Benjamin; Matuszkiewicz, Jennifer; Miura, Joanne; Miyake, Hiroshi; Natala, Srinivasa Reddy; Shi, Lihong; Takahashi, Masashi; Taylor, Ewan; Wyrick, Corey; Yano, Jason; Zalevsky, Jonathan; Nie, Zhe
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 24(2016)
• Page Start: 5947
• Page End: 5950
• Publication Date: 2016-12-15
• Subjects: SYK -- Kinase inhibitor -- Kinase selectivity -- Structure-based drug discovery -- Leukemia -- Lymphoma; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.10.087
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 candidateTAK-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.