Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 27, Issue 7, Pages 1370-1381Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.02.040
Keywords
Heat shock protein 90; HSP90; Hypoxia Inducible Factor-1a; HIF-1 alpha; Antitumor; Breast cancer; Deguelin
Funding
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HI12C1852, 1720340]
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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-1 alpha inhibition. Among them, compound 57 showed potent HIF-1 alpha 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 Cterminal inhibitor.
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