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

Yaoliang Sun; Zhiwen Chen; Guobin Liu; Xiaoai Chen; Zihan Shi; Huixu Feng; Lei Yu; Guodong Li; Ke Ding; He Huang; Zhang Zhang; Shilin Xu

doi:10.1016/j.bioorg.2023.107053

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. Epub 2023 Dec 25.

Authors

Yaoliang Sun¹, Zhiwen Chen², Guobin Liu³, Xiaoai Chen³, Zihan Shi⁴, Huixu Feng³, Lei Yu⁵, Guodong Li⁶, Ke Ding², He Huang⁷, Zhang Zhang⁸, Shilin Xu⁹

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: [email protected].
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: [email protected].
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: [email protected].

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).

MeSH terms

Cell Cycle Proteins*
Cell Line, Tumor
Humans
Protein Serine-Threonine Kinases
Protein-Tyrosine Kinases / antagonists & inhibitors
Threonine*
Tyrosine Kinase Inhibitors* / chemistry
Tyrosine Kinase Inhibitors* / pharmacology

Substances

Cell Cycle Proteins
Protein Serine-Threonine Kinases
Protein-Tyrosine Kinases
Threonine
TTK protein, human
Tyrosine Kinase Inhibitors