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These requirements make many pathogenic proteins \u201cundruggable.\u201d Here, we report a strategy to target these undruggable proteins: screening for compounds that directly bind to the undruggable target and rescue disease-relevant phenotypes. These compounds may suppress the target\u2019s pathogenic functions via direct binding to it. We applied this strategy to the mutant HTT protein, which is an undruggable protein that causes Huntington\u2019s disease (HD). We revealed desonide, an FDAapproved drug, as a possible lead compound for HD drug discovery.<\/jats:p>","DOI":"10.1073\/pnas.2114303119","type":"journal-article","created":{"date-parts":[[2022,3,2]],"date-time":"2022-03-02T11:45:46Z","timestamp":1646221546000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Suppression of toxicity of the mutant huntingtin protein by its interacting compound, desonide"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9125-3377","authenticated-orcid":false,"given":"Haikun","family":"Song","sequence":"first","affiliation":[{"name":"Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai 200438, China"},{"name":"Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University,  Guangzhou, Guangdong 511458, 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