Reducing off-Target hERG Activity of First-Generation DCN1-UBE2M Interaction Inhibitors: Design, Synthesis, and Structure−Activity Relationships

We previously reported a potent and orally available inhibitor (2, NAcM-OPT) of the DCN1-UBE2M protein interaction that targets the neddylation pathway to potentially regulate oncogenic transformation for the treatment of cancer. In vivo profiling of compound 2 revealed that, while it was potent, orally bioavailable, and inhibited growth of tumor xenografts in immunodeficient mice, it possessed significant off-target affinity for the human ether-a-go-go-related gene protein (hERG Ki = 750 nM), thereby significantly limiting its potential for development. Herein, we disclose the rational and systematic modification of compound 2 to reduce the affinity for hERG while maintaining its affinity for and activity against DCN1. These studies led to the discovery of compound 110, which exhibited equivalent biochemical and cellular potency to 2, improved physicochemical properties, and increased selectivity relative to hERG.