ITK 降解可阻断 T 细胞受体信号转导并克服 T 细胞淋巴瘤的治疗抵抗。
ITK degradation to block T cell receptor signaling and overcome therapeutic resistance in T cell lymphomas.
机构信息
Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
出版信息
Cell Chem Biol. 2023 Apr 20;30(4):383-393.e6. doi: 10.1016/j.chembiol.2023.03.007. Epub 2023 Apr 3.
Interleukin (IL)-2-inducible T cell kinase (ITK) is essential for T cell receptor (TCR) signaling and plays an integral role in T cell proliferation and differentiation. Unlike the ITK homolog BTK, no inhibitors of ITK are currently US Food and Drug Administration (FDA) approved. In addition, recent studies have identified mutations within BTK that confer resistance to both covalent and non-covalent inhibitors. Here, as an alternative strategy, we report the development of BSJ-05-037, a potent and selective heterobifunctional degrader of ITK. BSJ-05-037 displayed enhanced anti-proliferative effects relative to its parent inhibitor BMS-509744, blocked the activation of NF-kB/GATA-3 signaling, and increased the sensitivity of T cell lymphoma cells to cytotoxic chemotherapy both in vitro and in vivo. In summary, targeted degradation of ITK is a novel approach to modulate TCR signal strength that could have broad application for the investigation and treatment of T cell-mediated diseases.
白细胞介素（IL）-2 诱导的 T 细胞激酶（ITK）是 T 细胞受体（TCR）信号传导所必需的，并且在 T 细胞增殖和分化中起着重要作用。与 ITK 同源物 BTK 不同，目前没有美国食品和药物管理局（FDA）批准的 ITK 抑制剂。此外，最近的研究已经确定了 BTK 内的突变，这些突变赋予了对共价和非共价抑制剂的抗性。在这里，作为一种替代策略，我们报告了 ITK 的有效且选择性的双功能降解剂 BSJ-05-037 的开发。BSJ-05-037 相对于其母体抑制剂 BMS-509744 显示出增强的抗增殖作用，阻断了 NF-κB/GATA-3 信号的激活，并增加了 T 细胞淋巴瘤细胞对细胞毒性化疗的敏感性，无论是在体外还是体内。总之，靶向降解 ITK 是一种调节 TCR 信号强度的新方法，可广泛应用于 T 细胞介导的疾病的研究和治疗。
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