Using a multidisciplinary approach that involved structure-based drug design, synthesis, surface plasmon resonance, single-site directed mutagenesis, whole-cell patch-clamp electrophysiology, survival after oxidative stress in sensitized STHdhQ111/111 cells, co-immunoprecipitation experiments and in vivo assays in R6/1 mice, a Huntington’s disease mouse model, we have identified a promising new DREAM ligand, IQM-PC330, which was more potent and had longer lasting effects than the previously reported DREAM ligands. Here, KCNIP3 is linked to Huntington disease.