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

Betty Lam; Yasuyoshi Arikawa; Joshua Cramlett; Qing Dong; Ron de Jong; Victoria Feher; Charles E Grimshaw; Pamela J Farrell; Isaac D Hoffman; Andy Jennings; Benjamin Jones; Jennifer Matuszkiewicz; Joanne Miura; Hiroshi Miyake; Srinivasa Reddy Natala; Lihong Shi; Masashi Takahashi; Ewan Taylor; Corey Wyrick; Jason Yano; Jonathan Zalevsky; Zhe Nie

doi:10.1016/j.bmcl.2016.10.087

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. Epub 2016 Nov 2.

Authors

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

Affiliations

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.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Humans
Mice
Mice, Inbred C57BL
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / administration & dosage
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrrolidinones / administration & dosage
Pyrrolidinones / chemistry
Pyrrolidinones / pharmacology*
Structure-Activity Relationship
Syk Kinase / antagonists & inhibitors*
Syk Kinase / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Pyrrolidinones
TAK-659
Syk Kinase