2. Academic Validation
  3. Discovery of BP3 as an efficacious proteolysis targeting chimera (PROTAC) degrader of HSP90 for treating breast cancer

Discovery of BP3 as an efficacious proteolysis targeting chimera (PROTAC) degrader of HSP90 for treating breast cancer

  • Eur J Med Chem. 2022 Jan 15;228:114013. doi: 10.1016/j.ejmech.2021.114013.
Quanyu Liu 1,  Guihui Tu 2,  Yan Hu 3,  Qingna Jiang 2,  Jingwen Liu 2,  Shanshan Lin 2,  Zelei Yu 2,  Ge Li 2,  Xinhua Wu 2,  Yuanling Tang 2,  Xiuwang Huang 4,  Jianhua Xu 1,  Yang Liu 5,  Lixian Wu 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Institute of Materia Medica, 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; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China.
  • 3 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Department of Public Technology Service Center, Fujian Medical University (FMU), Fuzhou, PR China.
  • 4 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; Department of Public Technology Service Center, Fujian Medical University (FMU), Fuzhou, PR China.
  • 5 Institute of Materia Medica, Fujian Medical University (FMU), Fuzhou, PR China; Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University (FMU), Fuzhou, PR China; Department of Pharmacochemistry, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China.
  • 6 Department of Pharmacology, School of Pharmacy, Fujian Medical University (FMU), Fuzhou, PR China; Institute of Materia Medica, 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: 34864330 DOI: 10.1016/j.ejmech.2021.114013
Abstract

Heat shock protein 90 (HSP90) is involved in the stabilization and activation of oncoproteins, rendering it essential for oncogenic transformation. However, the HSP90 inhibitors evaluated to date have not led to the expected effects in Cancer therapy. Herein, we systematically described the design, synthesis, and evaluation of HSP90 degraders based upon the proteolysis-targeting chimera (PROTAC) strategy. The results showed that the candidate compound 16b (BP3) potently degraded HSP90 and effectively inhibited the growth of human breast Cancer cells. When used as a single agent, BP3 led to effective tumor suppression in mice. These findings demonstrate that our HSP90-targeting PROTAC strategy has potential novel applications in breast Cancer therapy.

Keywords

Breast cancer therapy; Heat shock protein 90; Protein degradation; Proteolysis target chimeric.

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