2. Academic Validation
  3. Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor

Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor

  • Bioorg Chem. 2024 Feb:143:107053. doi: 10.1016/j.bioorg.2023.107053.
Yaoliang Sun 1,  Zhiwen Chen 2,  Guobin Liu 3,  Xiaoai Chen 3,  Zihan Shi 4,  Huixu Feng 3,  Lei Yu 5,  Guodong Li 6,  Ke Ding 2,  He Huang 7,  Zhang Zhang 8,  Shilin Xu 9
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing 100049, China.
  • 5 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
  • 6 Macao Centre for Research and Development in Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
  • 7 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address: hhuang@simm.ac.cn.
  • 8 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China. Electronic address: zmoxue@163.com.
  • 9 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; University of Chinese Academy of Science, 19 Yuquan Road, Beijing 100049, China. Electronic address: slxu@simm.ac.cn.
PMID: 38159497 DOI: 10.1016/j.bioorg.2023.107053
Abstract

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 μM 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.

Keywords

Cancer; Covalent; Inhibitor; Threonine tyrosine kinase (TTK).

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z