Discovery of a simplified deguelin analog as an HSP90 C-terminal inhibitor for HER2-positive breast cancer

Cong Truong Nguyen, Minh Thanh La, Jihyae Ann, Gibeom Nam, Hyun Ju Park, Jung Min Park, Yoon Jae Kim, Ji Young Kim, Jae Hong Seo, Jeewoo Lee

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


A series of O-substituted analogs of the C-ring-truncated scaffold of deguelin designed as heat shock protein 90 (HSP90) C-terminal inhibitors were investigated as novel antitumor agents against human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Among the synthesized compounds, compound 37 displayed significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells with little cytotoxicity to normal cells. Mechanistic studies of compound 37 carried out by HSP90α C-terminal inhibitor screening, the induction of the heat shock response and downregulation of HSP90 client proteins indicated that the antitumor activity of 37 in breast cancer cells could be attributed to the destabilization and inactivation of HSP90 client proteins by the binding of 37 to the C-terminal domain of HSP90. A molecular docking study of compound 37 with a HSP90 homology model indicated that its S-isomer fit well in the ATP binding site of the C-terminal domain, forming key interactions.

Original languageEnglish
Article number128134
JournalBioorganic and Medicinal Chemistry Letters
Publication statusPublished - 2021 Aug 1

Bibliographical note

Funding Information:
This work was supported by a grant (HA170053000021) 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:
© 2021 Elsevier Ltd


  • Eat shock protein 90
  • HER2-positive breast cancer
  • Human epidermal growth factor receptor 2
  • Trastuzumab-resistant breast cancer

ASJC Scopus subject areas

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


Dive into the research topics of 'Discovery of a simplified deguelin analog as an HSP90 C-terminal inhibitor for HER2-positive breast cancer'. Together they form a unique fingerprint.

Cite this