Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor
文献类型：期刊论文
| 作者 | Sun, Yaoliang1; Chen, Zhiwen2; Liu, Guobin3; Chen, Xiaoai3; Shi, Zihan1,8; Feng, Huixu3; Yu, Lei4; Li, Guodong5; Ding, Ke2; Huang, He3,6,7 |
| 刊名 | BIOORGANIC CHEMISTRY
 |
| 出版日期 | 2024-02-01 |
| 卷号 | 143页码:16 |
| 关键词 | Inhibitor Cancer Threonine tyrosine kinase (TTK) Covalent |
| ISSN号 | 0045-2068 |
| DOI | 10.1016/j.bioorg.2023.107053 |
| 通讯作者 | Huang, He(hhuang@simm.ac.cn) ; Zhang, Zhang(zmoxue@163.com) ; Xu, Shilin(slxu@simm.ac.cn) |
| 英文摘要 | Threonine tyrosine kinase (TTK) is a critical component of the spindle assembly checkpoint and plays a pivotal role in mitosis. TTK has been identified as a potential therapeutic target for human cancers. Here, we describe our design, synthesis and evaluation of a class of covalent TTK inhibitors, exemplified by 16 (SYL1073). Compound 16 potently inhibits TTK kinase with an IC50 of 0.016 mu M and displays improved selectivity in a panel of kinases. Mass spectrometry analysis reveals that 16 covalently binds to the C604 cysteine residue in the hinge region of the TTK kinase domain. Furthermore, 16 achieves strong potency in inhibiting the growth of various human cancer cell lines, outperforming its relative reversible inhibitor, and eliciting robust downstream effects. Taken together, compound 16 provides a valuable lead compound for further optimization toward the development of drug for treatment of human cancers. |
| WOS关键词 | SPINDLE-ASSEMBLY CHECKPOINT ; CHROMOSOME MIS-SEGREGATION ; SMALL-MOLECULE INHIBITOR ; MPS1 ; EXPRESSION ; CFI-402257 ; GENES |
| 资助项目 | National Natural Science Foundation of China[22277128] ; National Natural Science Foundation of China[81973158] ; National Natural Science Foundation of China[22277125] ; National Natural Science Foundation of China[92253306] ; National Natural Science Foundation of China[81973164] ; Shanghai Sailing Program[22YF1457500] ; Shanghai Municipal Science and Technology Major Project |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001165655300001 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309551]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Huang, He; Zhang, Zhang; Xu, Shilin |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 2.Jinan Univ, Sch Pharm, Guangzhou City Key Lab Precis Chem Drug Dev, Int Cooperat Lab Tradit Chinese Med Modernizat & &, Guangzhou 510632, Peoples R China 3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 4.Tongji Univ, Tongji Univ Canc Ctr, Shanghai Peoples Hosp 10, Sch Med, Shanghai 200092, Peoples R China 5.Univ Macau, Inst Chinese Med Sci, Macao Ctr Res & Dev Chinese Med, State Key Lab Qual Res Chinese Med, Macau 999078, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China 7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 8.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Sun, Yaoliang,Chen, Zhiwen,Liu, Guobin,et al. Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor[J]. BIOORGANIC CHEMISTRY,2024,143:16. |
| APA | Sun, Yaoliang.,Chen, Zhiwen.,Liu, Guobin.,Chen, Xiaoai.,Shi, Zihan.,...&Xu, Shilin.(2024).Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor.BIOORGANIC CHEMISTRY,143,16. |
| MLA | Sun, Yaoliang,et al."Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor".BIOORGANIC CHEMISTRY 143(2024):16. |
入库方式： OAI收割
来源：上海药物研究所
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