2. Academic Validation
  3. Discovery of X10g as a selective PROTAC degrader of Hsp90α protein for treating breast cancer

Discovery of X10g as a selective PROTAC degrader of Hsp90α protein for treating breast cancer

  • Eur J Med Chem. 2023 Jul 28;260:115690. doi: 10.1016/j.ejmech.2023.115690.
Qingna Jiang 1,  Minghai Fu 2,  Yuanling Tang 1,  Ge Li 1,  Guihui Tu 1,  Xinhua Wu 1,  Qiurong Wu 1,  Xiuwang Huang 3,  Jianhua Xu 1,  Yang Liu 4,  Lixian Wu 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China.
  • 2 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Department of Pharmacochemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China.
  • 3 Department of Public Technology Service Center, Fujian Medical University (FMU), Fuzhou, PR China.
  • 4 Department of Pharmacochemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University (FMU), Fuzhou, PR China. Electronic address: [email protected].
  • 5 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China. Electronic address: [email protected].
PMID: 37619298 DOI: 10.1016/j.ejmech.2023.115690
Abstract

Heat shock protein 90 (HSP90), a highly conserved and widely expressed molecular chaperone, is mainly responsible for maintaining the correct folding of client proteins and is closely related to the stability and activation of tumour-related proteins. Hsp90α, the major isoform of HSP90, can promote tumour cell migration and metastasis, and is abundantly secreted in highly invasive tumours. To date, most pan-Hsp90 inhibitors have been limited in their applications due to high toxicity. Herein, we described the candidate compound X10g based on a proteolysis-targeting chimaera (PROTAC) strategy that potently and selectively degraded Hsp90α. The results showed that X10g inhibited tumours better with lower toxicity in vivo. These findings demonstrate that synthesized selective Hsp90α degrader X10g provides a new strategy for breast Cancer therapy.

Keywords

Breast cancer therapy; Heat shock protein 90α; PROTACs; Selective protein degradation.

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