2. Academic Validation
  3. Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK)

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

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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