Heat shock protein 90 (Hsp90) is a potential oncogenic target. However, Hsp90 inhibitors in clinical trial induce heat shock response, resulting in drug resistance and inefficiency. In this study, we designed and synthesized a series of novel triazine derivatives (<b>A1</b>-<b>26</b>, <b>B1</b>-<b>13</b>, <b>C1</b>-<b>23</b>) as Hsp90 inhibitors. Compound <b>A14</b> directly bound to Hsp90 in a different manner from traditional Hsp90 inhibitors, and degraded client proteins, but did not induce the concomitant activation of Hsp72. Importantly, <b>A14</b> exhibited the most potent anti-proliferation ability by inducing autophagy, with the IC<sub>50</sub> values of 0.1 μM and 0.4 μM in A549 and SK-BR-3 cell lines, respectively. The <i>in</i> <i>vivo</i> study demonstrated that <b>A14</b> could induce autophagy and degrade Hsp90 client proteins in tumor tissues, and exhibit anti-tumor activity in A549 lung cancer xenografts. Therefore, the compound <b>A14</b> with potent antitumor activity and unique pharmacological characteristics is a novel Hsp90 inhibitor for developing anticancer agent without heat shock response.
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