Small molecule inhibits T-cell acute lymphoblastic leukaemia oncogenic interaction through conformational modulation of LMO2.
Small molecule inhibits T-cell acute lymphoblastic leukaemia oncogenic interaction through conformational modulation of LMO2.
复制标题
DOI：
10.18632/oncotarget.27580
复制
发表时间：
2020-05-12
期刊：
影响因子：
--
通讯作者：
Mancini, Erika J
中科院分区：
文献类型：
--
作者：
Milton-Harris, Leanne;Jeeves, Mark;Mancini, Erika J
LIM only protein 2（LMO 2）是造血发育的关键因子，其在T细胞前体中的异位表达与T细胞急性淋巴细胞白血病（T-ALL）的发病有关。在T-ALL背景下，LMO 2通过与红细胞特异性转录因子SCL/TAL 1结合并隔离T细胞分化通常所需的E蛋白转录因子来驱动致癌进展。形成这种致癌蛋白质-蛋白质相互作用（PPI）的关键要求是LMO 2的构象灵活性。在这里，我们确定了SCL-LMO 2 PPI的一种小分子抑制剂，它通过与LMO 2直接结合来阻碍体外相互作用。生物物理分析表明，这种抑制剂的作用，通过构象调制的LMO 2的机制。重要的是，这项工作已经鉴定出SCL-LMO 2 PPI的小分子抑制剂，这可以为开发治疗T-ALL的新药提供起点。这些结果表明，基于小分子调节蛋白质构象的类似方法可用于其他致癌PPI的治疗靶向。
Ectopic expression in T-cell precursors of LIM only protein 2 (LMO2), a key factor in hematopoietic development, has been linked to the onset of T-cell acute lymphoblastic leukaemia (T-ALL). In the T-ALL context, LMO2 drives oncogenic progression through binding to erythroid-specific transcription factor SCL/TAL1 and sequestration of E-protein transcription factors, normally required for T-cell differentiation. A key requirement for the formation of this oncogenic protein-protein interaction (PPI) is the conformational flexibility of LMO2. Here we identify a small molecule inhibitor of the SCL-LMO2 PPI, which hinders the interaction in vitro through direct binding to LMO2. Biophysical analysis demonstrates that this inhibitor acts through a mechanism of conformational modulation of LMO2. Importantly, this work has led to the identification of a small molecule inhibitor of the SCL-LMO2 PPI, which can provide a starting point for the development of new agents for the treatment of T-ALL. These results suggest that similar approaches, based on the modulation of protein conformation by small molecules, might be used for therapeutic targeting of other oncogenic PPIs.