Bruton’s tyrosine kinase (BTK) is critical for B-cell receptor signaling and related to many types of human cancers. However, the drug resistance and off-target effect of present traditional BTK inhibitors occurred over time. As a new strategy for drug development, the proteolysis targeting chimera (PROTAC) has been proved to target varieties of proteins. Here SPB5208 (4-(2-(2-(2-(2-(3-(4-amino-3-(4-phenoxy phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)ethoxy)ethoxy)ethoxy)ethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione) was synthesized as a new PROTAC degradation agent of BTK by linking Ibrutinib and Thalidomide. In vitro study indicated that SPB5208 reduced the BTK enzyme activity with high selectivity and inhibited effectively cancer cell proliferation. More than that, SPB5208 induced BTK protein degradation through a proteasome- and CRBN- dependent manner in JeKo-1 cells. In addition, SPB5208 was also confirmed to induce significantly BTK protein degradation in vivo. Thus, this study provides a new pharmacological tool for further study of new BTK PROTAC and their mechanism of action in physiological environment.

中文翻译：

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通过PROTAC有针对性地选择性降解Bruton酪氨酸激酶

布鲁顿的酪氨酸激酶（BTK）对于B细胞受体信号传导至关重要，并且与许多类型的人类癌症有关。然而，目前的传统BTK抑制剂的耐药性和脱靶作用随时间而发生。作为药物开发的新策略，靶向嵌合体的蛋白水解（PROTAC）已被证明可靶向多种蛋白质。在这里SPB5208（4-（2-（2-（2-（2-（3-（4-氨基-3-（4-苯氧基苯基）-1H-吡唑并[3,4-d]嘧啶-1-基）通过将依鲁替尼（Ibrutinib）与沙利度胺。体外研究表明，SPB5208高选择性降低了BTK酶的活性，并有效抑制了癌细胞的增殖。比那更多的，SPB5208在JeKo-1细胞中通过蛋白酶体和CRBN依赖性方式诱导BTK蛋白降解。另外，还证实了SPB5208在体内显着诱导BTK蛋白降解。因此，本研究为进一步研究新的BTK PROTAC及其在生理环境中的作用机理提供了新的药理学工具。