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including the regulation of Ca<jats:sup>2+<\/jats:sup> and protein homeostasis. We recently showed that reduced DREAM expression or blockade of DREAM activity by repaglinide is neuroprotective in Huntington\u2019s disease (HD). Here we used structure-based drug design to guide the identification of IQM-PC330, which was more potent and had longer lasting effects than repaglinide to inhibit DREAM in cellular and <jats:italic>in vivo<\/jats:italic> HD models. We disclosed and validated an unexplored ligand binding site, showing Tyr118 and Tyr130 as critical residues for binding and modulation of DREAM activity. IQM-PC330 binding de-repressed c-fos gene expression, silenced the DREAM effect on K<jats:sub>V<\/jats:sub>4.3 channel gating and blocked the ATF6\/DREAM interaction. 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