Milton-Harris Leanne, Jeeves Mark, Walker Sarah A, Ward Simon E, Mancini Erika J
School of Life Sciences, Biochemistry Department, University of Sussex, Falmer, Brighton, BN1 9QG, United Kingdom.
Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, United Kingdom.
Oncotarget. 2020 May 12;11(19):1737-1748. doi: 10.18632/oncotarget.27580.
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 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.
造血发育中的关键因子——仅含LIM结构域蛋白2（LMO2）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，LMO2通过与红系特异性转录因子SCL/TAL1结合并隔离E蛋白转录因子来驱动致癌进程，而E蛋白转录因子是T细胞分化所必需的。形成这种致癌性蛋白质-蛋白质相互作用（PPI）的一个关键要求是LMO2的构象灵活性。在此，我们鉴定出一种SCL-LMO2 PPI的小分子抑制剂，它通过直接结合LMO2来阻碍这种相互作用。生物物理分析表明，这种抑制剂通过对LMO2进行构象调节的机制发挥作用。重要的是，这项工作已导致鉴定出一种SCL-LMO2 PPI的小分子抑制剂，它可为开发治疗T-ALL的新药提供一个起点。这些结果表明，基于小分子对蛋白质构象的调节的类似方法可能用于其他致癌性PPI的治疗靶向。
