Discovery of novel anti-breast cancer agents derived from deguelin as inhibitors of heat shock protein 90 (HSP90). Issue 17 (1st September 2020)

• Record Type: Journal Article
• Authors: Nguyen, Cong-Truong; Ann, Jihyae; Sahu, Raghaba; Byun, Woong Sub; Lee, Sangkook; Nam, Gibeom; Park, Hyun-Ju; Park, Soeun; Kim, Yoon-Jae; Kim, Ji Young; Seo, Jae Hong; Lee, Jeewoo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 17(2020)
• Publication Date: 2020-09-01
• Subjects: HER2-positive breast cancer -- Human epidermal growth factor receptor 2 -- Heat shock protein 90 -- Deguelin; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127374
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.