Discovering High Potent Hsp90 Inhibitors as Antinasopharyngeal Carcinoma Agents through Fragment Assembling Approach

Mengyang  Xu; Chao  Zhao; Biying  Zhu; Liangyue  Wang; Huihao  Zhou; Daoguang  Yan; Qiong  Gu; Jun  Xu

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Discovering High Potent Hsp90 Inhibitors as Antinasopharyngeal Carcinoma Agents through Fragment Assembling Approach

机译：通过片段组装方法发现高效的HSP90抑制剂作为抗胰腺癌癌剂

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Hsp90 is a new promising target for cancer treatment. Many inhibitors have been discovered as therapeutic agents, and some have passed Phase I and II. However, no one is approved by FDA yet. Novel and druggable Hsp90 inhibitors are still demanding. Here, we report a new way to discover high potent Hsp90 inhibitors as antinasopharyngeal carcinoma agents through assembling fragments. With chemotyping analysis, we extract seven chemotypes from 3482 known Hsp90 inhibitors, screen 500 fragments that are compatible with the chemotypes, and confirm 15 anti-Hsp90 fragments. Click chemistry is employed to construct 172 molecules and synthesize 21 compounds among them. The best inhibitor 3d was further optimized and resulted in more potent 4f (IC_(50) = 0.16 μM). In vitro and in vivo experiments confirmed that 4f is a promising agent against nasopharyngeal carcinoma. This study may provide a strategy in discovering new ligands against targets without well-understood structures.

机译：Hsp90是治疗癌症的一个新靶点。许多抑制剂已被发现作为治疗剂，其中一些已通过I期和II期。然而，还没有人得到FDA的批准。新型的、可药用的Hsp90抑制剂仍然是一项艰巨的任务。在这里，我们报告了一种通过组装片段发现高效Hsp90抑制剂作为抗鼻咽癌药物的新方法。通过化学分型分析，我们从3482个已知的Hsp90抑制剂中提取了7个化学型，筛选了500个与这些化学型相容的片段，并确认了15个抗Hsp90片段。点击化学被用于构建172个分子，并合成其中21个化合物。对最佳抑制剂3d进行了进一步优化，得到了更有效的4f（IC_50）=0.16μM）体外和体内实验证实4f是一种有前途的抗鼻咽癌药物。这项研究可能提供了一种策略，可以发现新的配体来对抗结构不明的目标。

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《Journal of Medicinal Chemistry》 |2021年第4期|共14页
作者
Mengyang Xu; Chao Zhao; Biying Zhu; Liangyue Wang; Huihao Zhou; Daoguang Yan; Qiong Gu; Jun Xu;
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作者单位

Research Center for Drug Discovery School of Pharmaceutical Sciences Sun Yat-Sen University;

Research Center for Drug Discovery School of Pharmaceutical Sciences Sun Yat-Sen University;

Department of Biotechnology College of Life Science and Technology Jinan University;

Research Center for Drug Discovery School of Pharmaceutical Sciences Sun Yat-Sen University;

Research Center for Drug Discovery School of Pharmaceutical Sciences Sun Yat-Sen University;

Department of Biotechnology College of Life Science and Technology Jinan University;

Research Center for Drug Discovery School of Pharmaceutical Sciences Sun Yat-Sen University;

Research Center for Drug Discovery School of Pharmaceutical Sciences Sun Yat-Sen University;

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正文语种 eng
中图分类药学;
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6. Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design [J] . Dymock BW, Barril X, Brough PA, Journal of Medicinal Chemistry . 2005,第13期

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Discovering High Potent Hsp90 Inhibitors as Antinasopharyngeal Carcinoma Agents through Fragment Assembling Approach

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