The interaction of E2 enzyme Ubc12 and E3 enzyme Dcn1 in NEDD8 pathway facilitated the transfer of NEDD8 from Ubc12 to cullins, which dramatically accelerated the activity of cullin-RING. Starting from the native, 12-residue peptide derived from UBC12 protein, which binds to DCN1 with a moderate affinity, we have successfully designed a series of highly potent, druglike small-molecule inhibitors of UBC12-DCN1 interaction with low nanomolar binding affinities through structure-guided design and extensive medicinal chemistry campaign. Significantly, employing our lead compound as a chemical probe, we for the first time discovered the specificity and function of DCN1 protein and provide proof of concept for the DCN1 inhibitors as specific modulator of CRLs activity. Our designed compounds serve as an excellent chemical probe for basic research to investigate NEDD8 pathway-related biology.

Structure-based design of highly potent small-molecule inhibitors of DCN1-UBC12 protein-protein interaction

253rd National Meeting (2017)

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