Modulate Cullin-RING E3 ubiquitin ligases by small molecule agents

项目摘要 最近我们发现了一组抑制Cullin-RING E3泛素连接酶4的类药物小分子 （CRL 4）。我们已经发现这些分子对白血病细胞系的一个亚群是有毒的，这些细胞系表达非常高的 低水平的CRL 4组分cullin 4.此外，CRL 4抑制剂显示出抗肿瘤活性， 实验小鼠这些初步发现表明一个有趣的可能性，一些低淘汰4- 表达白血病细胞系易受我们新发现的CRL 4抑制剂的影响，因此可以用于 选择性癌症治疗 在这个项目中，我们建议使用合成化学来改进CRL 4抑制剂，并了解其作用机制。 小分子化合物如何抑制CRL 4的分子基础。最后，我们将开发两种细胞- 和基于动物的临床前模型，以评估CRL 4抑制剂对肿瘤的抗癌潜力。 以低Cullin 4丰度为特征的白血病亚群。这些信息对于发展中国家的 改善白血病治疗的新策略。

Project Summary Recently we have discovered a group of drug-like small molecules that inhibit Cullin-RING E3 ubiquitin ligase 4 (CRL4). We have found that these molecules are toxic to a subset of leukemia cell lines, which express very low levels of the CRL4 component cullin 4. Moreover, the CRL4 inhibitors exhibit anti-tumor activity in experimental mice. These preliminary findings suggest an interesting possibility that some low-cullin 4- expressing leukemia lines are vulnerable to our newly discovered CRL4 inhibitors and thus can be exploited for selective cancer therapies. In this project, we propose to improve CRL4 inhibitors using synthetic chemistry and to understand the molecular basis of how the small molecule compounds act to inhibit CRL4. Finally, we will develop both cell- and animal-based pre-clinical models to evaluate the anti-cancer potential for the CRL4 inhibitors against a subset of leukemia that are characterized by low cullin 4 abundance. Such information is critical for developing new strategy to improve the treatment of leukemia.