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Bioorg Med Chem Lett. 2016 Dec 15;26(24):5947-5950. doi: 10.1016/j.bmcl.2016.10.087. Epub 2016 Nov 2.

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

Author information

1
Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA. Electronic address: betty.lam@takeda.com.
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.

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

PMID:
27839918
DOI:
10.1016/j.bmcl.2016.10.087
[Indexed for MEDLINE]

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