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环E3泛素连接酶4的类药物小分子 (CRL4)。我们已经发现，这些分子对白血病细胞系的一部分有毒性，这些细胞株非常表达 低水平的CRL4成分cullin 4。此外，CRL4抑制剂显示出抗肿瘤活性 实验小鼠。这些初步发现表明了一种有趣的可能性，即一些低淘汰率的4- 表达白血病的细胞系对我们新发现的CRL4抑制剂很敏感，因此可以利用这些药物来治疗 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CRL4抑制剂，并了解 小分子化合物如何作用于抑制CRL4的分子基础。最后，我们将发展这两个细胞- 以动物为基础的临床前模型来评估CRL4抑制剂的抗癌潜力 白血病的一个亚群，其特征是Ccullin 4丰度低。这样的信息对于开发 改进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.