Liu Peng, Chen Xiangling, Zhu Jianming, Li Bo, Chen Zhaoqiang, Wang Guimin, Sun Haiguo, Xu Zhijian, Zhao Zhixin, Zhou Chen, Xie Chengying, Lou Liguang, Zhu Weiliang
Key Laboratory of Receptor Research Drug Discovery and Design Center Shanghai Institute of Materia Medica Chinese Academy of Sciences 555 Zuchongzhi Road Shanghai 201203 China.
University of Chinese Academy of Sciences No.19 A Yuquan Road Beijing 100049 China.
ChemistryOpen. 2019 Mar 28;8(3):344-353. doi: 10.1002/open.201900055. eCollection 2019 Mar.
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 (-, -, -) as Hsp90 inhibitors. Compound 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, exhibited the most potent anti-proliferation ability by inducing autophagy, with the IC values of 0.1 μM and 0.4 μM in A549 and SK-BR-3 cell lines, respectively. The study demonstrated that could induce autophagy and degrade Hsp90 client proteins in tumor tissues, and exhibit anti-tumor activity in A549 lung cancer xenografts. Therefore, the compound with potent antitumor activity and unique pharmacological characteristics is a novel Hsp90 inhibitor for developing anticancer agent without heat shock response.
热休克蛋白90（Hsp90）是一个潜在的致癌靶点。然而，处于临床试验阶段的Hsp90抑制剂会引发热休克反应，导致耐药性和无效性。在本研究中，我们设计并合成了一系列新型三嗪衍生物（-、-、-）作为Hsp90抑制剂。化合物 以与传统Hsp90抑制剂不同的方式直接与Hsp90结合，并降解客户蛋白，但不会诱导Hsp72的伴随激活。重要的是， 通过诱导自噬表现出最有效的抗增殖能力，在A549和SK-BR-3细胞系中的IC值分别为0.1 μM和0.4 μM。 研究表明， 可诱导肿瘤组织中的自噬并降解Hsp90客户蛋白，并在A549肺癌异种移植模型中表现出抗肿瘤活性。因此，具有强大抗肿瘤活性和独特药理特性的化合物 是一种新型的Hsp90抑制剂，可用于开发无热休克反应的抗癌药物。
