A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation

Haibin Zhou, Jianfeng Lu, Liu Liu, Denzil Bernard, Chao-Yie Yang, Ester Fernandez-Salas, Krishnapriya Chinnaswamy, Stephanie Layton, Jeanne Stuckey, Qing Yu, Weihua Zhou, Zhenqiang Pan, Yi Sun and Shaomeng Wang ()
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Haibin Zhou: University of Michigan
Jianfeng Lu: University of Michigan
Liu Liu: University of Michigan
Denzil Bernard: University of Michigan
Chao-Yie Yang: University of Michigan
Ester Fernandez-Salas: University of Michigan
Krishnapriya Chinnaswamy: University of Michigan
Stephanie Layton: University of Michigan
Jeanne Stuckey: University of Michigan
Qing Yu: Zhejiang University School of Medicine
Weihua Zhou: University of Michigan
Zhenqiang Pan: Mount Sinai School of Medicine
Yi Sun: University of Michigan
Shaomeng Wang: University of Michigan

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract The Cullin-RING E3 ubiquitin ligases (CRLs) regulate homeostasis of ~20% of cellular proteins and their activation require neddylation of their cullin subunit. Cullin neddylation is modulated by a scaffolding DCN protein through interactions with both the cullin protein and an E2 enzyme such as UBC12. Here we report the development of DI-591 as a high-affinity, cell-permeable small-molecule inhibitor of the DCN1–UBC12 interaction. DI-591 binds to purified recombinant human DCN1 and DCN2 proteins with K i values of 10–12 nM, and disrupts the DCN1–UBC12 interaction in cells. Treatment with DI-591 selectively converts cellular cullin 3 into an un-neddylated inactive form with no or minimum effect on other cullin members. Our data firmly establish a previously unrecognized specific role of the DCN1–UBC12 interaction for cellular neddylation of cullin 3. DI-591 is an excellent probe compound to investigate the role of the cullin 3 CRL ligase in biological processes and human diseases.

Date: 2017
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DOI: 10.1038/s41467-017-01243-7

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