| Literature DB >> 27839918 |
Betty Lam1, Yasuyoshi Arikawa2, Joshua Cramlett3, Qing Dong4, Ron de Jong5, Victoria Feher6, Charles E Grimshaw5, Pamela J Farrell5, Isaac D Hoffman5, Andy Jennings5, Benjamin Jones5, Jennifer Matuszkiewicz7, Joanne Miura5, Hiroshi Miyake2, Srinivasa Reddy Natala8, Lihong Shi7, Masashi Takahashi2, Ewan Taylor5, Corey Wyrick5, Jason Yano9, Jonathan Zalevsky10, Zhe Nie7.
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. Copyright ÂEntities:
Keywords: Kinase inhibitor; Kinase selectivity; Leukemia; Lymphoma; SYK; Structure-based drug discovery
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Year: 2016 PMID： 27839918 DOI： 10.1016/j.bmcl.2016.10.087
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823