2. Academic Validation
  3. Discovering High Potent Hsp90 Inhibitors as Antinasopharyngeal Carcinoma Agents through Fragment Assembling Approach

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

  • J Med Chem. 2021 Feb 25;64(4):2010-2023. doi: 10.1021/acs.jmedchem.0c01521.
Mengyang Xu 1 2,  Chao Zhao 1 3,  Biying Zhu 2,  Liangyue Wang 1,  Huihao Zhou 1,  Daoguang Yan 2,  Qiong Gu 1,  Jun Xu 1 4
Affiliations

Affiliations

  • 1 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2 Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
  • 3 Shenzhen Cell Inspire Therapeutics Co., Ltd., Shenzhen 518101, China.
  • 4 School of Biotechnology and Health Sciences, Wuyi University, 99 Yingbin Road, Jiangmen 529020, China.
PMID: 33543615 DOI: 10.1021/acs.jmedchem.0c01521
Abstract

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 (IC50 = 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.

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