2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Chiral-Proline Derivatives as Novel HSP90 Inhibitors

Design, Synthesis, and Biological Evaluation of Chiral-Proline Derivatives as Novel HSP90 Inhibitors

  • ACS Med Chem Lett. 2025 Jan 22;16(2):301-310. doi: 10.1021/acsmedchemlett.4c00550.
Chao Zhang 1,  Shuang Cui 2,  Jialin Mu 3,  Kexin Liu 1,  Yuanxun Wang 4,  Hongyu Zhao 1,  Yuguang Mu 5,  Youming Zhang 1 6,  Xiaobo Wan 4,  Chun Song 1 6
Affiliations

Affiliations

  • 1 Laboratory for Food and Medicine Homologous Natural Resources Development and Utilization, Dezhou University, Dezhou City 253023, Shandong Province, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan City 250012, Shandong Province, China.
  • 3 Jinan Maternal and Child Care Hospital, No.2, Jingsan Road, Shizhong District, Jinan City 250000, Shandong Province, China.
  • 4 Computational Medicine Beijing Co., Ltd, Building 16, Beilun Industrial Park, 9 North Yongteng Road, Haidian District, Beijing 100094, China.
  • 5 School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551 Singapore.
  • 6 State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
PMID: 39967617 DOI: 10.1021/acsmedchemlett.4c00550
Abstract

Heat shock protein 90 (HSP90) is a promising target for oncology therapeutics. Over the past decades, several small molecule inhibitors have demonstrated significant antitumor activity in clinical trials. However, nearly all HSP90 inhibitors in clinical trials have failed due to toxicity or insufficient efficacy. By leveraging crystal structures and current knowledge, we synthesized and evaluated a series of novel derivatives with potent HSP90 inhibitory activity, optimized from resorcinol-based (2R, 4R)-4-phenylproline. These derivatives underwent SAR analysis, leading to the discovery of compounds 16t and 20m, which exhibit strong HSP90 binding affinity and antiproliferative effects against MCF-7, HCT116, SKBr3, K562, and A549 cell lines. Nevertheless, further optimization of derivatives 16t and 20m was required to enhance their oral bioavailability and isoform selectivity. Our findings provide valuable insights for the ongoing research into selective HSP90α inhibitors and lay a foundation for developing next-generation HSP90α inhibitors and antitumor agents.

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