Discovery of novel anti-breast cancer agents derived from deguelin as inhibitors of heat shock protein 90 (HSP90)

Cong Truong Nguyen, Jihyae Ann, Raghaba Sahu, Woong Sub Byun, Sangkook Lee, Gibeom Nam, Hyun Ju Park, Soeun Park, Yoon Jae Kim, Ji Young Kim, Jae Hong Seo, Jeewoo Lee

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12 Citations (Scopus)


A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.

Original languageEnglish
Article number127374
JournalBioorganic and Medicinal Chemistry Letters
Issue number17
Publication statusPublished - 2020 Sept 1

Bibliographical note

Funding Information:
This work was supported by a grant (HI12C1852, 1720340) from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea.

Publisher Copyright:
© 2020 Elsevier Ltd


  • Deguelin
  • HER2-positive breast cancer
  • Heat shock protein 90
  • Human epidermal growth factor receptor 2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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