Modulate Cullin-RING E3 ubiquitin ligases by small molecule agents

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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.