文章：

验证一种靶向PDE6D-RAS相互作用的小分子抑制剂具有良好的抗白血病效应

Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects

原文发布日期：2022-04-14

DOI: 10.1038/s41408-022-00663-z

类型: Article

开放获取: 是

英文摘要：

RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.
 

摘要翻译： 

高危白血病中常见的RAS基因突变与复发及化疗耐药性相关。直接靶向RAS蛋白的治疗尝试大多未能成功。然而，由于RAS介导的细胞转化依赖于通过RAS相关C3肉毒杆菌毒素底物（RAC）小GTP酶的信号传导，我们推测靶向RAC可能成为治疗RAS突变肿瘤的有效策略。本文报道了多种能够抑制急性淋巴细胞白血病细胞系中RAC活化的小分子化合物。其中DW0254在RAS突变细胞中展现出良好的抗白血病活性。通过化学蛋白质组学和生物物理方法，我们确定该化合物的作用靶点为磷酸二酯酶6δ亚基（PDE6D）的疏水口袋——这是一种已知的RAS分子伴侣。DW0254处理后通过磷脂酰肌醇-3-激酶/AKT依赖性机制抑制RAS向细胞膜的定位，该过程与RAC抑制密切相关。我们的研究为PDE6D介导的运输在RAS依赖性RAC激活及白血病细胞存活中的重要性提供了新的见解。

原文链接：

Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects