期刊论文

Chen, Xiaojuan;Chen, Yongheng

英文

Bioorganic & Medicinal Chemistry Letters

0960-894X

2021

34

127757

10.1016/j.bmcl.2020.127757

We thank the staff from BL17U beamline and BL19U of the Shanghai Synchrotron Radiation Facility (SSRF) for helping with data collection. This work was supported by grants from National Natural Science Foundation of China (Y.C., project numbers 81570537 and 81974074), and the Science and Technology Planning Project of Hunan Province (Y.C., project number 2018TP1017).

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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 insi...