Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Histology and Embryology, Institute of Clinical Anatomy & Reproductive Medicine, University of South China Hengyang, Hunan 421001, China.
Bioorg Med Chem Lett. 2021 Feb 15;34:127757. doi: 10.1016/j.bmcl.2020.127757. Epub 2020 Dec 24.
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.
伊布替尼是一种 BTK 靶向的不可逆抑制剂。在这项研究中，我们通过质谱和晶体学证明，伊布替尼以非共价的方式强力抑制 SRC 的活性。S345C 突变使 SRC 与伊布替尼发生共价结合，并恢复伊布替尼对看门突变体的效力。伊布替尼/SRC 的共晶结构表明，SRC 的 Ser345 并未与伊布替尼形成共价键，导致效力降低，并丧失克服 SRC 看门突变的能力。X 射线晶体学研究还为为什么伊布替尼对不同激酶的看门突变体表现出不同的作用提供了结构上的见解。
