Characterization of ibrutinib as a non-covalent inhibitor of SRC-family kinases

[Display omitted] Ibrutinib is a BTK-targeted irreversible inhibitor. In this study, we demonstrate that ibrutinib potently inhibits SRC activity in a non-covalent manner via mass spectrometry and crystallography. The S345C mutation renders SRC to bind covalently with ibrutinib, and restores the pot...

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Published inBioorganic & medicinal chemistry letters Vol. 34; p. 127757
Main Authors Guo, Ming, Dai, Shuyan, Wu, Daichao, Duan, Yankun, Li, Jun, Qu, Lingzhi, Jiang, Longying, Chen, Zhuchu, Chen, Xiaojuan, Chen, Yongheng
Format Journal Article
LanguageEnglish
Published England Elsevier Ltd 15.02.2021
Subjects
Gatekeeper mutation
Ibrutinib
Non-covalent
SRC
Non-covalent
SRC
Ibrutinib
Gatekeeper mutation
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Summary:[Display omitted] Ibrutinib is a BTK-targeted irreversible inhibitor. In this study, we demonstrate that ibrutinib potently inhibits SRC activity in a non-covalent manner via mass spectrometry and crystallography. The S345C mutation renders SRC to bind covalently with ibrutinib, and restores the potency of ibrutinib against the gatekeeper mutant. The co-crystal structure of ibrutinib/SRC shows Ser345 of SRC did not form covalent bond with ibrutinib, leading to a decrease of potency and loss of the ability to overcome the gatekeeper mutation of SRC. The X-ray crystallographic studies also provide structural insight into why ibrutinib behaves differently against gatekeeper mutants of different kinases.
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ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2020.127757