Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK)

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Lam, Betty¹  Arikawa, Yasuyoshi²  Cramlett, Joshua³  Dong, Qing⁴  de Jong, Ron¹  Feher, Victoria⁵  Grimshaw, Charles E.¹  Farrell, Pamela J.¹  Hoffman, Isaac D.¹  Jennings, Andy¹  Jones, Benjamin¹  Matuszkiewicz, Jennifer⁶  Miura, Joanne¹  Miyake, Hiroshi²  Natala, Srinivasa Reddy⁷  Shi, Lihong⁶  Takahashi, Masashi²  Taylor, Ewan¹  Wyrick, Corey¹  Yano, Jason⁸  Zalevsky, Jonathan⁹  Nie, Zhe⁶ 

[1] Takeda Calif Inc, 10410 Sci Ctr Dr, San Diego, CA 92121 USA

[2] Takeda Pharmaceut Co Ltd, 26-1 Muraoka Higashi 2 Chome, Fujisawa, Kanagawa 2518555, Japan

[3] PolySci Consulting Inc, 4624 Aragon Dr, San Diego, CA 92115 USA

[4] FronThera US Pharmaceut, 11526 Sorrento Valley Rd,Suite D, San Diego, CA 92121 USA

[5] Schrodinger Inc, 5820 Oberlin Dr,Ste 203, San Diego, CA 92121 USA

[6] Celgene Quanticel Res, 9393 Towne Ctr Dr,Suite 110, San Diego, CA 92121 USA

[7] Neuropore Therapies, 10835 Rd Cure,Suite 230, San Diego, CA 92121 USA

[8] Beryllium Discovery, 3 Preston Ct, Bedford, MA 01730 USA

[9] Nektar Therapeut, 455 Miss Bay Blvd South, San Francisco, CA 94158 USA

关键词: SYK;    Kinase inhibitor;    Kinase selectivity;    Structure-based drug discovery;    Leukemia;    Lymphoma;   

DOI  :  10.1016/j.bmcl.2016.10.087

来源: Elsevier

【 摘 要 】

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. TAIL-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 (C) 2016 Elsevier Ltd. All rights reserved.

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