文章：

多激酶抑制剂TG02通过双重作用机制诱导慢性淋巴细胞白血病细胞凋亡并阻断B细胞受体信号通路

The multi-kinase inhibitor TG02 induces apoptosis and blocks B-cell receptor signaling in chronic lymphocytic leukemia through dual mechanisms of action

原文发布日期：2021-03-13

DOI: 10.1038/s41408-021-00436-0

类型: Article

开放获取: 是

英文摘要：

The constitutive activation of B-cell receptor (BCR) signaling, together with the overexpression of the Bcl-2 family anti-apoptotic proteins, represents two hallmarks of chronic lymphocytic leukemia (CLL) that drive leukemia cell proliferation and sustain their survival. TG02 is a small molecule multi-kinase inhibitor that simultaneously targets both of these facets of CLL pathogenesis. First, its inhibition of cyclin-dependent kinase 9 blocked the activation of RNA polymerase II and transcription. This led to the depletion of Mcl-1 and rapid induction of apoptosis in the primary CLL cells. This mechanism of apoptosis was independent of CLL prognostic factors or prior treatment history, but dependent on the expression of BAX and BAK. Second, TG02, which inhibits the members of the BCR signaling pathway such as Lck and Fyn, blocked BCR-crosslinking-induced activation of NF-κB and Akt, indicating abrogation of BCR signaling. Finally, the combination of TG02 and ibrutinib demonstrated moderate synergy, suggesting a future combination of TG02 with ibrutinib, or use in patients that are refractory to the BCR antagonists. Thus, the dual inhibitory activity on both the CLL survival pathway and BCR signaling identifies TG02 as a unique compound for clinical development in CLL and possibly other B cell malignancies.
 

摘要翻译： 

B细胞受体（BCR）信号通路的组成性激活，连同Bcl-2家族抗凋亡蛋白的过度表达，是慢性淋巴细胞白血病（CLL）的两大特征，驱动白血病细胞增殖并维持其生存。TG02是一种小分子多激酶抑制剂，能同时靶向CLL发病机制的这两个方面。首先，其对细胞周期蛋白依赖性激酶9的抑制阻断了RNA聚合酶II的激活和转录过程，导致Mcl-1蛋白耗竭并迅速诱导原代CLL细胞凋亡。这种凋亡机制独立于CLL预后因素或既往治疗史，但依赖于BAX和BAK蛋白的表达。其次，TG02通过抑制BCR信号通路成员（如Lck和Fyn），阻断了BCR交联诱导的NF-κB和Akt激活，表明其可消除BCR信号传导。最后，TG02与依鲁替尼联用显示出中等协同效应，这提示未来可将TG02与依鲁替尼联合使用，或用于对BCR拮抗剂耐药的患者。因此，TG02对CLL生存通路和BCR信号通路的双重抑制活性，使其成为临床治疗CLL及其他B细胞恶性肿瘤的独特候选化合物。

原文链接：

The multi-kinase inhibitor TG02 induces apoptosis and blocks B-cell receptor signaling in chronic lymphocytic leukemia through dual mechanisms of action