Dialing hERG out of a DCN1–UBE2M inhibitor without losing potency
- The earlier tool compound NAcM-OPT blocked the DCN1–UBE2M interaction, was orally available and slowed xenograft growth, but carried significant hERG affinity that stalled development.
- The authors systematically modified the scaffold to cut hERG binding while keeping DCN1 engagement.
- Lead compound 110 matched the parent in biochemical and cellular potency, with better physicochemical properties and improved selectivity against hERG.
💡 Points
This is the unglamorous but necessary second act: a validated PPI chemotype that was dead on cardiac safety, rescued by SAR alone. The takeaway for anyone with a basic, lipophilic PPI binder is that hERG can often be engineered out without giving up the pharmacophore, so check your own series before abandoning it.