筛选抑制肾癌生长的SPOP靶向小分子抑制剂

Renal cell carcinoma (RCC) is highly resistant to radiation therapy and chemotherapy. The current targeted drugs produce only low objective responses in patients. Therefore, it's important to develop drugs that are more targeted and have fewer side effects for RCC treatment. We have demonstrated SPOP, an E3 ubiquitin ligase adaptor, overexpressed in clear cell renal cell carcinoma (ccRCC) and accumulated in the cytoplasm. Cytoplasmic SPOP mediates ubiquitination and degradation of multiple key regulators, including the tumor suppressor PTEN and the ERK phosphates DUSP7, promotes cell proliferation and tumorigenesis. Knockdown of SPOP specifically kills ccRCC cells but not normal cells, suggesting it may be a promising candidate for therapeutic intervention. In this project, incorporating the structural data of SPOP-substrate complex crystal, we will perform bioinformatics computational design and high throughput screens to identify small molecule inhibitors targeting SPOP. And we will perform cell biology assays to screen out a small molecule inhibitor with best anti-RCC cancer cells effects. Then we will perform bare mouse xenograft experiments to explore the potential ability of the inhibitor to kill renal cell carcinoma. Our studies will find a new targeted drug selectly killing ccRCC. And our long-term goal is developing a platform targeting SPOP for kidney cancer treatment.

肾癌对放疗和化疗不敏感，已有靶向药物作用效果有限。因此急需研发靶向效果更好的治疗药物。我们已证实，在肾癌中，泛素化连接蛋白SPOP过量表达并累积于细胞质。胞质中的SPOP能介导PTEN、DUSP7的泛素化和降解，从而加速细胞增殖，促进肿瘤产生。抑制SPOP能特异杀死肿瘤细胞，但对正常细胞没有伤害，暗示SPOP是一个潜在的特异的药物靶标。本项目将综合利用生物信息学及多种实验技术手段，根据SPOP与底物复合物晶体结构，设计筛选靶向SPOP的小分子抑制剂，并进行细胞水平实验验证，筛选出最佳候选小分子药物，之后进行裸鼠移植瘤实验，探索此小分子抑制剂治疗人肾癌移植瘤的潜能。我们的研究将开发一种高效特异肾癌靶向治疗药物，长期目标是通过靶向SPOP达到治疗肾癌的目的。

近年来肾癌发病率上升幅度在恶性肿瘤中排名第一。而肾癌对放疗和化疗均不敏感。因此，发现并确证治疗肾癌特异性药物作用新靶标十分重要。我们以SPOP与蛋白质相互作用为靶标，根据SPOP识别底物多肽的复合物晶体结构的特点，获得了能够与SPOP结合的小分子化合物，该化合物特异地抑制肾癌细胞株生长而对正常细胞株不影响,进一步体内生化实验证明此小分子化合物能抑制SPOP与底物蛋白质的结合，让一些抑癌蛋白避免被降解，并且最终抑制肾癌细胞株的生长,同时发现SPOP小分子抑制剂对人肾癌裸鼠移植瘤的治疗效果不错,并且对小鼠毒副作用小。这一研究为SPOP能否作为透明细胞肾癌药物靶标进行了药理功能确证，为SPOP抑制剂的发现并运用于治疗肾癌指明了新方向。相关结果发表在 Cancer Cell上。