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Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors

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Affiliated Author(s)
하은영
Alternative Author(s)
Ha, Eun Young
Journal Title
European Journal of Medicinal Chemistry
ISSN
0223-5234
Issued Date
2018
Keyword
Drug designHsp90 inhibitorLung cancerResistanceSmall molecule
Abstract
Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90α inhibitory activity with IC50 value of 5.3 nM and an excellent growth inhibition with GI50 value of 0.42 μM against non-small cell lung cancer cells, H1975. Compound 30f effectively reduces the expression levels of Hsp90 client proteins including Her2, EGFR, Met, Akt, and c-Raf. Consequently, compound 30f promotes substantial cleavages of PARP, Caspase 3, and Caspase 8, indicating that 30f induces cancer cell death via apoptotic pathway. Moreover, cytochrome P450 assay indicates that compound 30f has weak inhibitory effect on the activities of five major P450 isoforms (IC50 > 5 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between 30f and the substrate drugs of the five major P450 isoforms are not expected. Compound 30f also inhibits the tumor growth in a mouse xenograft model bearing subcutaneous H1975 without noticeable abnormal behavior and body weight changes. The immunostaining and western immunoblot analysis of EGFR, Met, Akt in xenograft tissue sections of tumor further demonstrate a good agreement with the in vitro results.
Department
Dept. of Biochemistry (생화학)
Publisher
School of Medicine (의과대학)
Citation
Sun You Park et al. (2018). Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors. European Journal of Medicinal Chemistry, 143, 390–401. doi: 10.1016/j.ejmech.2017.11.054
Type
Article
ISSN
0223-5234
DOI
10.1016/j.ejmech.2017.11.054
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/41173
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Biochemistry (생화학)
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