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Recent clinical trial failures of antisense oligonucleotide candidates in HD have demonstrated the need for new therapeutic approaches. Here, we developed a novel in-silico fragment scanning approach across the surface of mutant huntingtin (mHTT) polyQ and predicted four hit compounds. Two rounds of compound analoging using a strategy of testing structurally similar compounds in an affinity assay rapidly identified GLYN122. In vitro, GLYN122 directly binds and reduces mHTT and induces autophagy in neurons. In vivo, our results confirm that GLYN122 can reduce mHTT in the cortex and striatum of the R\/2 mouse model of Huntington\u2019s disease and subsequently improve motor symptoms. 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SME is the Chief Executive Officer (CEO) of Galyan Bio, Inc. CYE is a professor at ETH Zurich but also a co-founder and shareholder of Avea Life AG, and is on the Scientific Advisory Board of Maximon AG and Galyan Bio, Inc. KL is Managing Director of Bicoll GmbH and Director and General Manager of Bicoll Biotechnology (Shanghai) Co. Ltd. All other authors do not have any conflicts of interest to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"19642"}}