title: Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
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.
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA. Electronic address: betty.lam@takeda.com.
authors.forename: Betty
authors.initials: B
authors.lastname: Lam
authors.affiliation: Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yasuyoshi
authors.initials: Y
authors.lastname: Arikawa
authors.affiliation: PolyScientific Consulting Inc., 4624 Aragon Dr, San Diego, CA 92115, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Cramlett
authors.affiliation: FronThera US Pharmaceuticals, 11526 Sorrento Valley Road, Suite D, San Diego, CA 92121, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: de Jong
authors.affiliation: Schrödinger, Inc., 5820 Oberlin Drive, Ste. 203, San Diego, CA 92121, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Feher
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Grimshaw
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Farrell
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Isaac D
authors.initials: ID
authors.lastname: Hoffman
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Andy
authors.initials: A
authors.lastname: Jennings
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Jones
authors.affiliation: Celgene Quanticel Research, 9393 Towne Center Drive, Suite 110, San Diego, CA 92121, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Matuszkiewicz
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Miura
authors.affiliation: Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.affiliation: Neuropore Therapies, 10835 Road to Cure, Suite 230, San Diego, CA 92121, USA.
authors.forename: Srinivasa Reddy
authors.initials: SR
authors.lastname: Natala
authors.affiliation: Celgene Quanticel Research, 9393 Towne Center Drive, Suite 110, San Diego, CA 92121, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Ewan
authors.initials: E
authors.lastname: Taylor
authors.affiliation: Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Wyrick
authors.affiliation: Beryllium Discovery, 3 Preston Ct., Bedford, MA 01730, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Yano
authors.affiliation: Nektar Therapeutics, 455 Mission Bay Boulevard South, San Francisco, CA 94158, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Zalevsky
authors.affiliation: Celgene Quanticel Research, 9393 Towne Center Drive, Suite 110, San Diego, CA 92121, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Nie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011760:Pyrrolidinones; C000620859:TAK-659; D000072377:Syk Kinase
keywords: Kinase inhibitor; Kinase selectivity; Leukemia; Lymphoma; SYK; Structure-based drug discovery