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Normally, huntingtin (HTT) prevents this binding, allowing expressing of REST target genes. Here, we aimed to identify HTT mimetics that disrupt REST complex formation in HD. From a structure\u2010based virtual screening of 7 million molecules, we selected 94 compounds predicted to interfere with REST complex formation by targeting the PAH1 domain of <jats:styled-content style=\"fixed-case\">mSIN<\/jats:styled-content>3b. Primary screening using <jats:italic>DiaNRSELuc8<\/jats:italic> cells revealed two classes of compounds causing a greater than two\u2010fold increase in luciferase. In particular, quinolone\u2010like compound 91 (C91) at a non\u2010toxic nanomolar concentration reduced <jats:styled-content style=\"fixed-case\">mSIN<\/jats:styled-content>3b nuclear entry and occupancy at the RE1\/NRSE within the <jats:italic>Bdnf<\/jats:italic> locus, and restored brain\u2010derived neurotrophic factor (BDNF) protein levels in HD cells. The <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> levels of other RE1\/NRSE\u2010regulated genes were similarly increased while non\u2010REST\u2010regulated genes were unaffected. C91 stimulated REST\u2010regulated gene expression in HTT\u2010knockdown Zebrafish and increased BDNF <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> in the presence of mutant HTT. Thus, a combination of virtual screening and biological approaches can lead to compounds reducing REST complex formation, which may be useful in HD and in other pathological conditions.<\/jats:p><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc12348-fig-0007-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><jats:p>Dysregulation of REST and its target genes have been implicated in Huntington's disease. We have coupled structured\u2010based virtual screening approaches to biological assays and selected molecules that interfere with the repressor complex REST\u2010mSIN3b. In particular, at the non\u2010toxic dose, compound C91 is able to increase neuronal gene transcription and to reverse low Bdnf mRNA levels in HD models.<\/jats:p>","DOI":"10.1111\/jnc.12348","type":"journal-article","created":{"date-parts":[[2013,6,26]],"date-time":"2013-06-26T07:37:15Z","timestamp":1372232235000},"page":"22-35","source":"Crossref","is-referenced-by-count":48,"title":["Binding of the repressor complex REST\u2010<scp>mSIN<\/scp>3b by small molecules restores neuronal gene transcription in Huntington's disease models"],"prefix":"10.1111","volume":"127","author":[{"given":"Paola","family":"Conforti","sequence":"first","affiliation":[{"name":"Department of BioSciences Universit\u00e0 degli Studi di Milano Milano Italy"},{"name":"Center for Stem Cell Research Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Zuccato","sequence":"additional","affiliation":[{"name":"Department of BioSciences Universit\u00e0 degli Studi di Milano Milano Italy"},{"name":"Center for Stem Cell Research Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Germano","family":"Gaudenzi","sequence":"additional","affiliation":[{"name":"Department of BioSciences Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Ieraci","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Biomolecular Science Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Camnasio","sequence":"additional","affiliation":[{"name":"Department of BioSciences Universit\u00e0 degli Studi di Milano Milano Italy"},{"name":"Center for Stem Cell Research Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noel J.","family":"Buckley","sequence":"additional","affiliation":[{"name":"King's College London Institute of Psychiatry Centre for the Cellular Basis of Behavior London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Mutti","sequence":"additional","affiliation":[{"name":"Department of BioSciences Universit\u00e0 degli Studi di Milano Milano Italy"},{"name":"Center for Stem Cell Research Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Cotelli","sequence":"additional","affiliation":[{"name":"Department of BioSciences Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Contini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Science Division of General and Organic Chemistry \u201cA. Marchesini\u201d Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cattaneo","sequence":"additional","affiliation":[{"name":"Department of BioSciences Universit\u00e0 degli Studi di Milano Milano Italy"},{"name":"Center for Stem Cell Research Universit\u00e0 degli Studi di Milano Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,7,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)07497-4"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00269-07"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1042\/BST0371270"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.9.1647"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0401827101"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2010.02.003"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2011.02.059"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-06-02112.2003"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.08.012"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20290"},{"key":"e_1_2_8_12_1","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/gt.2012.84","article-title":"In vivo delivery of DN:REST improves transcriptional changes of REST\u2010regulated genes in HD mice","volume":"20","author":"Conforti P.","year":"2012","journal-title":"Gene Ther."},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.10.015"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.08.032"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6039-08.2009"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.10349"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm8015987"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1039\/c2md20328f"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611704104"},{"key":"e_1_2_8_20_1","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1158\/1535-7163.MCT-04-0228","article-title":"Many human medulloblastoma tumors overexpress repressor element\u20101 silencing transcription (REST)\/neuron\u2010restrictive silencer factor, which can be functionally countered by REST\u2010VP16","volume":"4","author":"Fuller G. 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