Novobiocin Analogs That Inhibit the MAPK Pathway
View/ Open
Issue Date
2016-02-11Author
Hall, Jessica Ann
Seedarala, Sahithi
Zhao, Huiping
Garg, Gaurav
Ghosh, Suman
Blagg, Brian S. J.
Publisher
American Chemical Society
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Metadata
Show full item recordAbstract
Heat shock protein 90 (Hsp90) inhibition by modulation of the N-or C-terminal binding site has become an attractive strategy for the development of anti-cancer chemotherapeutics. The first Hsp90 C-terminus inhibitor, novobiocin, manifested a relatively high IC50 value of ~700 μM. Therefore, investigation of the novobiocin scaffold has led to analogs with improved antiproliferative activity (nanomolar concentrations) against several cancer cell lines. During these studies, novobiocin analogs that do not inhibit Hsp90 were identified; however, these analogs demonstrated potent anti-proliferative activity. Compound 2, a novobiocin analog, was identified as a MAPK pathway signaling disruptor that lacked Hsp90 inhibitory activity. In addition, structural modifications of compound 2 were identified that segregated Hsp90 inhibition from MAPK signaling disruption. These studies indicate that compound 2 represents a novel scaffold for disruption of MAPK pathway signaling and may serve as a useful structure for the generation of new anti-cancer agents.
Description
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/acs.jmedchem.5b01354.
Collections
Citation
Hall, J. A., Seedarala, S., Zhao, H., Garg, G., Ghosh, S., & Blagg, B. S. J. (2016). Novobiocin Analogs That Inhibit the MAPK Pathway. Journal of Medicinal Chemistry, 59(3), 925–933. http://doi.org/10.1021/acs.jmedchem.5b01354
Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.