Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel.
J Enzyme Inhib Med Chem. 2021 Dec;36(1):401-409. doi: 10.1080/14756366.2020.1871337.
The C2-WW-HECT-domain E3 ubiquitin ligase SMURF2 emerges as an important regulator of diverse cellular processes. To date, SMURF2-specific modulators were not developed. Here, we generated and investigated a set of SMURF2-targeting synthetic peptides and peptidomimetics designed to stimulate SMURF2's autoubiquitination and turnover via a disruption of the inhibitory intramolecular interaction between its C2 and HECT domains. The results revealed the effects of these molecules both and at the nanomolar concentration range. Moreover, the data showed that targeting of SMURF2 with either these modifiers or -specific shRNAs could accelerate cell growth in a cell-context-dependent manner. Intriguingly, a concomitant cell treatment with a selected SMURF2-targeting compound and the DNA-damaging drug etoposide markedly increased the cytotoxicity produced by this drug in growing cells. Altogether, these findings demonstrate that SMURF2 can be druggable through its self-destructive autoubiquitination, and inactivation of SMURF2 might be used to affect cell sensitivity to certain anticancer drugs.
C2-WW-HECT 结构域 E3 泛素连接酶 SMURF2 作为多种细胞过程的重要调节剂而出现。迄今为止，尚未开发出针对 SMURF2 的特异性调节剂。在这里，我们生成并研究了一组针对 SMURF2 的合成肽和肽类似物，这些肽和肽类似物旨在通过破坏其 C2 和 HECT 结构域之间的抑制性分子内相互作用来刺激 SMURF2 的自泛素化和周转。结果显示，这些分子在纳摩尔浓度范围内均具有 和 的作用。此外，数据表明，用这些修饰剂或 -特异性 shRNA 靶向 SMURF2 可以以细胞上下文依赖的方式加速细胞生长。有趣的是，同时用选定的靶向 SMURF2 的化合物和 DNA 损伤药物依托泊苷处理细胞会显著增加该药物在生长细胞中的细胞毒性。总之，这些发现表明可以通过 SMURF2 的自破坏泛素化来对 SMURF2 进行药物治疗，并且抑制 SMURF2 的失活可能用于影响细胞对某些抗癌药物的敏感性。
