BTK激酶是治疗B细胞淋巴瘤的一个重要靶点。近来美国FDA已经批准了BTK激酶抑制剂Ibrutinib用于套细胞淋巴瘤和慢性淋巴细胞白血病的治疗。我们前期开发了一个与Ibrutinib作用机制相同的BTK激酶不可逆抑制剂QL47, 尽管两者都通过与BTK激酶中的Cys481形成共价键而发挥药效，但是其作用效果在BTK蛋白自磷酸化、对细胞内BTK的下游信号通路影响、癌症细胞系增殖抑制以及病人的原代细胞增殖抑制上却有很大的差异。通过广泛的前期探索，我们认为这极有可能是由于不同药物与BTK激酶发生作用后所引起的不同构象变化而产生的，而核磁共振技术是研究此类蛋白动态变化的首选手段。因此，我们拟通过高场核磁共振结构生物学的方法，结合分子生物学等多种研究手段，从结构变化的角度探究这些药效差异的机理，为进一步揭示BTK激酶及其信号通路在B细胞淋巴瘤中的作用以及开发新的BTK激酶靶向药物提供理论依据。

BTK kinase is one of the most important and validated drug discovery targets for B-cell lymphoma. In Nov. 2013 and Feb. 2014, USFDA approved irreversible BTK inhibitor Ibrutinib (PCI-32765) for the clinical use against mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), respectively. Recently we have developed an irreversible BTK kinase inhibitor QL47 that presumably shares a similar mechanism with Ibrutinib by irreversibly forming a covalent bond with Cys481 located in the hinge binding area of the ATP binding pocket. However, we found that their pharmacological effects are quite different regarding to the autophosphorylation of BTK in vitro, effect of the blockage of BTK downstream signaling, anti-proliferative effect of B-cell malignant cell lines and the anti-proliferation effect on the patient derived primary cells. By excluding other kinase mediated off-target effects, we envisioned that one of the most possible reasons for this difference may be due to the different conformational change induced by the drug binding and subsequent covalent bond formation. NMR is one of the most suitable techniques for such study. Therefore, we plan to use the high magnetic field NMR methods, combing with the molecular biology and chemical biology techniques, to explore its mechanism from the structural point of view, which will help us to further interpret the role of BTK dysregulation in B-cell lymphoma and pave the way to develop next generation BTK kinase inhibitor drugs.