Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 89, Issue -, Pages 442-466Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.10.034
Keywords
Heat shock protein 90; Hsp90 C-Terminal inhibitors; Biphenyl; Structure-activity relationship; Breast cancer
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Funding
- NIH/NCI [CA120458]
- NSF [9512331]
- AIRC (Associazione Italiana Ricerca sul Cancro) [IG.11775]
- MIUR [PB.P05]
- CNR
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Modulation of Hsp90 C-terminal function represents a promising therapeutic approach for the treatment of cancer and neurodegenerative diseases. Current drug discovery efforts toward Hsp90 C-terminal inhibition focus on novobiocin, an antibiotic that was transformed into an Hsp90 inhibitor. Based on structural information obtained during the development of novobiocin derivatives and molecular docking studies, scaffolds containing a biphenyl moiety in lieu of the coumarin ring present in novobiocin were identified as new Hsp90 C-terminal inhibitors. Structure activity relationship studies produced new derivatives that inhibit the proliferation of breast cancer cell lines at nanomolar concentrations, which corresponded directly with Hsp90 inhibition. (C) 2014 Elsevier Masson SAS. All rights reserved.
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