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

  • Bioorg Med Chem Lett. 2016 Dec 15;26(24):5947-5950. doi: 10.1016/j.bmcl.2016.10.087.
Betty Lam  1 ,  Yasuyoshi Arikawa  2 ,  Joshua Cramlett  3 ,  Qing Dong  4 ,  Ron de Jong  5 ,  Victoria Feher  6 ,  Charles E Grimshaw  5 ,  Pamela J Farrell  5 ,  Isaac D Hoffman  5 ,  Andy Jennings  5 ,  Benjamin Jones  5 ,  Jennifer Matuszkiewicz  7 ,  Joanne Miura  5 ,  Hiroshi Miyake  2 ,  Srinivasa Reddy Natala  8 ,  Lihong Shi  7 ,  Masashi Takahashi  2 ,  Ewan Taylor  5 ,  Corey Wyrick  5 ,  Jason Yano  9 ,  Jonathan Zalevsky  10 ,  Zhe Nie  7
Affiliations
  • 1. Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA. Electronic address: [email protected].
  • 2. Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 3. PolyScientific Consulting Inc., 4624 Aragon Dr, San Diego, CA 92115, USA.
  • 4. FronThera US Pharmaceuticals, 11526 Sorrento Valley Road, Suite D, San Diego, CA 92121, USA.
  • 5. Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
  • 6. Schrödinger, Inc., 5820 Oberlin Drive, Ste. 203, San Diego, CA 92121, USA.
  • 7. Celgene Quanticel Research, 9393 Towne Center Drive, Suite 110, San Diego, CA 92121, USA.
  • 8. Neuropore Therapies, 10835 Road to Cure, Suite 230, San Diego, CA 92121, USA.
  • 9. Beryllium Discovery, 3 Preston Ct., Bedford, MA 01730, USA.
  • 10. Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA 94158, USA.
PMID: 27839918 DOI: 10.1016/j.bmcl.2016.10.087
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.

Keywords
Kinase inhibitor; Kinase selectivity; Leukemia; Lymphoma; SYK; Structure-based drug discovery.
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