Investigation of B,C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors for use as anti-breast cancer agents

Ho Shin Kim, Van Hai Hoang, Mannkyu Hong, Kyung Chul Kim, Jihyae Ann, Cong Truong Nguyen, Ji Hae Seo, Hoon Choi, Jun Yong Kim, Kyu Won Kim, Woong Sub Byun, Sangkook Lee, Seungbeom Lee, Young Ger Suh, Jie Chen, Hyun Ju Park, Tae Min Cho, Ji Young Kim, Jae Hong Seo, Jeewoo Lee

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6 Citations (Scopus)

Abstract

On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor.

Original languageEnglish
Pages (from-to)1370-1381
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume27
Issue number7
DOIs
Publication statusPublished - 2019 Apr 1

Keywords

  • Antitumor
  • Breast cancer
  • Deguelin
  • HIF-1 α
  • HSP90
  • Heat shock protein 90
  • Hypoxia Inducible Factor-1α

ASJC Scopus subject areas

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

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  • Cite this

    Kim, H. S., Hoang, V. H., Hong, M., Chul Kim, K., Ann, J., Nguyen, C. T., Seo, J. H., Choi, H., Yong Kim, J., Kim, K. W., Sub Byun, W., Lee, S., Lee, S., Suh, Y. G., Chen, J., Park, H. J., Cho, T. M., Kim, J. Y., Seo, J. H., & Lee, J. (2019). Investigation of B,C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors for use as anti-breast cancer agents. Bioorganic and Medicinal Chemistry, 27(7), 1370-1381. https://doi.org/10.1016/j.bmc.2019.02.040