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Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach
Author(s) -
Chini Maria G.,
Malafronte Nicola,
Vaccaro Maria C.,
Gualtieri Maria J.,
Vassallo Antonio,
Vasaturo Michele,
Castellano Sabrina,
Milite Ciro,
Leone Antonietta,
Bifulco Giuseppe,
De Tommasi Nunziatina,
Dal Piaz Fabrizio
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201602242
Subject(s) - hsp90 , heat shock protein , hela , docking (animal) , geldanamycin , chemistry , drug discovery , small molecule , virtual screening , moiety , computational biology , structure–activity relationship , chaperone (clinical) , atpase , biochemistry , combinatorial chemistry , cell , enzyme , biology , stereochemistry , in vitro , medicine , nursing , pathology , gene
The identification of inhibitors of Hsp90 is currently a primary goal in the development of more effective drugs for the treatment of various types of multidrug resistant malignancies. In an attempt to identify new small molecules modulating the activity of Hsp90, we screened a small library of tetranortriterpenes. A high‐affinity interaction with Hsp90 inducible form was uncovered for eight of these compounds, five of which are described here for the first time. By monitoring the ATPase activity and the citrate synthase thermal induced aggregation, compound 1 (cedrelosin A), 3 (7α‐limonylacetate), and 5 (cedrelosin B), containing a limonol moiety, were found to be the most effective in compromising the Hsp90α chaperone activity. Consistent with these findings, the three compounds caused a depletion of c‐Raf and pAkt Hsp90 client proteins in HeLa and MCF/7 cell lines. Induced fit docking protocol and molecular dynamics were used to rationalize the structural basis of the biological activity of the limonol derivatives. Taken together, these results point to limonol‐derivatives as promising scaffolds for the design of novel Hsp90α inhibitors.