Lam Betty, Arikawa Yasuyoshi, Cramlett Joshua, Dong Qing, de Jong Ron, Feher Victoria, Grimshaw Charles E, Farrell Pamela J, Hoffman Isaac D, Jennings Andy, Jones Benjamin, Matuszkiewicz Jennifer, Miura Joanne, Miyake Hiroshi, Natala Srinivasa Reddy, Shi Lihong, Takahashi Masashi, Taylor Ewan, Wyrick Corey, Yano Jason, Zalevsky Jonathan, Nie Zhe
Takeda California, Inc., 10410 Science Center Drive, San Diego, CA 92121, USA.
Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Bioorg Med Chem Lett. 2016 Dec 15;26(24):5947-5950. doi: 10.1016/j.bmcl.2016.10.087. Epub 2016 Nov 2.
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.
脾酪氨酸激酶（SYK）是一种非受体细胞质酪氨酸激酶，主要在造血细胞中表达。SYK是多种炎症细胞（包括B细胞、肥大细胞、巨噬细胞和中性粒细胞）的关键介质，因此是治疗炎症性疾病和肿瘤适应症的一种有吸引力的方法。利用内部共晶体结构信息和基于结构的药物设计，我们设计并优化了一系列新型杂芳基吡咯烷酮SYK抑制剂，从而筛选出了候选开发药物TAK-659。TAK-659目前正在进行针对晚期实体瘤和淋巴瘤恶性肿瘤的I期临床试验、与纳武单抗联合用于晚期实体瘤的Ib期研究以及针对复发/难治性急性髓细胞白血病的Ib/II期试验。
