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Targeting Hsp90 has had therapeutic success in both solid and hematological malignancies, which has inspired more studies to identify new Hsp90 inhibitors with improved clinical efficacy. Using a fragment-based approach and subsequent structural optimization guided by medicinal chemistry principles, we identified the novel compound <jats:bold>CPUY201112<\/jats:bold> as a potent Hsp90 inhibitor. It binds to the ATP-binding pocket of Hsp90 with a kinetic dissociation (K<jats:sub>d<\/jats:sub>) constant of 27\u2009\u00b1\u20092.3\u2009nM. It also exhibits potent <jats:italic>in vitro<\/jats:italic> antiproliferative effects in a range of solid tumor cells. In MCF-7 cells with high Hsp90 expression, <jats:bold>CPUY201112<\/jats:bold> induces the degradation of Hsp90 client proteins including HER-2, Akt and c-RAF. We prove that treating MCF-7 cells with <jats:bold>CPUY201112<\/jats:bold> results in cell cycle arrest and apoptosis through the wild-type (wt) p53 pathway. <jats:bold>CPUY201112<\/jats:bold> also synergizes with <jats:bold>Nutlin-3a<\/jats:bold> to induce cancer cell apoptosis. <jats:bold>CPUY201112<\/jats:bold> significantly inhibited the growth of MCF-7 xenografts in nude mice without apparent body weight loss. These results demonstrate that <jats:bold>CPUY201112<\/jats:bold> is a novel Hsp90 inhibitor with potential use in treating wild-type p53 related cancers.<\/jats:p>","DOI":"10.1038\/srep19004","type":"journal-article","created":{"date-parts":[[2016,1,8]],"date-time":"2016-01-08T11:45:33Z","timestamp":1452253533000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["CPUY201112, a novel synthetic small-molecule compound and inhibitor of heat shock protein Hsp90, induces p53-mediated apoptosis in MCF-7 cells"],"prefix":"10.1038","volume":"6","author":[{"given":"Xiao-Li","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi-chao","family":"Bao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-Min","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Ke","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-ye","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-lian","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng-chen","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-li","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Jin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi-Dong","family":"You","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao-Peng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,1,8]]},"reference":[{"key":"BFsrep19004_CR1","doi-asserted-by":"publisher","first-page":"e358","DOI":"10.1016\/S1470-2045(13)70169-4","volume":"14","author":"R Garcia-Carbonero","year":"2013","unstructured":"Garcia-Carbonero, R., Carnero, A. & Paz-Ares, L. 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