Discovery of small molecule modulators of the Cullin-RING E3 ubiquitin ligases

To date there is no drug-lead like small molecule modulators targeting the catalytic activity of Cullin-RING E3 ubiquitin ligases (CRLs). To meet this challenge we have developed a fluorescence (Förster) resonance energy transfer (FRET)-based assay that requires the catalytic activity of a CRL’s core ligase complex. We have then optimized this assay into a robust high throughput-screening (HTS) platform. Preliminary HTS has resulted in identification of a score of compounds that bind to CRL’s core ligase complex and inhibit its activity. The newly identified CRL core ligase inhibitor exhibits a broad cytotoxic activity against a panel of solid and hematopoietic tumor cell lines, suggesting therapeutic potential for this class of inhibitors.