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The absence of a crystal structure of the Hsp90<jats:sup>N<\/jats:sup>\u2013Debio0932 complex, however, has impeded further structural optimization of Debio0932 and understanding of the molecular-interaction mechanism. Here, a high-resolution crystal structure of the Hsp90<jats:sup>N<\/jats:sup>\u2013Debio0932 complex was successfully determined (resolution limit 2.20\u2005\u00c5; PDB entry 6lr9) by X-ray diffraction and the molecular-interaction mechanism was analysed in detail, which suggested that Debio0932 suppresses cancer cells by accommodating itself in the ATP-binding pocket of Hsp90<jats:sup>N<\/jats:sup>, disabling its molecular-chaperone capability. The results of a thermal shift assay (\u0394<jats:italic>T<\/jats:italic>\n                  <jats:sub>m<\/jats:sub> = 8.83 \u00b1 0.90\u00b0C) and isothermal titration calorimetry (<jats:italic>K<\/jats:italic>\n                  <jats:sub>d<\/jats:sub> = 15.50 \u00b1 1.30\u2005n<jats:italic>M<\/jats:italic>) indicated strong binding and favourable thermodynamic changes in the binding of Hsp90<jats:sup>N<\/jats:sup> and Debio0932. Based on the crystal structure of the complex and on molecular-interaction analysis, 30 new Debio0932 derivatives were designed and nine new derivatives exhibited increased binding to Hsp90<jats:sup>N<\/jats:sup>, as determined by molecular-docking evaluation. Additionally, Debio0932 suppressed cell proliferation (IC<jats:sub>50<\/jats:sub> values of 3.26 \u00b1 2.82\u2005\u00b5<jats:italic>M<\/jats:italic> for A549, 20.33 \u00b1 5.39\u2005\u00b5<jats:italic>M<\/jats:italic> for H1299 and 3.16 \u00b1 1.04\u2005\u00b5<jats:italic>M<\/jats:italic> for H1975), induced cell-cycle arrest and promoted apoptosis in three non-small-cell lung cancer (NSCLC) cell lines. These results provide novel perspectives and guidance for the development of new anti-NSCLC drugs based on the lead compound Debio0932.<\/jats:p>","DOI":"10.1107\/s2059798320014990","type":"journal-article","created":{"date-parts":[[2020,12,17]],"date-time":"2020-12-17T11:24:46Z","timestamp":1608204286000},"page":"86-97","update-policy":"https:\/\/doi.org\/10.1107\/cm_01","source":"Crossref","is-referenced-by-count":3,"title":["Complex crystal structure determination and anti-non-small-cell lung cancer activity of the Hsp90<sup>N<\/sup> inhibitor Debio0932"],"prefix":"10.1107","volume":"77","author":[{"given":"Wei","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Jin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Xia","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Quan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi-Sheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Hua","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Ling","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"329","published-online":{"date-parts":[[2021,1,1]]},"reference":[{"key":"dw5212_bb1","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/dta.1798","volume":"7","author":"Andreotti","year":"2015","journal-title":"Drug Test. 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