Abstract
Hsp90 C-terminal domain (CTD) inhibitors are promising novel agents for cancer treatment, as they do not induce the heat shock response associated with Hsp90 N-terminal inhibitors. One challenge associated with CTD inhibitors is the lack of a co-crystallized complex, requiring the use of predicted allosteric apo pocket, limiting structure-based (SB) design approaches. To address this, a unique approach that enables the derivation and analysis of interactions between ligands and proteins from molecular dynamics (MD) trajectories was used to derive pharmacophore models for virtual screening (VS) and identify suitable binding sites for SB design. Furthermore, ligand-based (LB) pharmacophores were developed using a set of CTD inhibitors to compare VS performance with the MD derived models. Virtual hits identified by VS with both SB and LB models were tested for antiproliferative activity. Compounds 9 and 11 displayed antiproliferative activities in MCF-7 and Hep G2 cancer cell lines. Compound 11 inhibited Hsp90-dependent refolding of denatured luciferase and induced the degradation of Hsp90 clients without the concomitant induction of Hsp70 levels. Furthermore, compound 11 offers a unique scaffold that is promising for the further synthetic optimization and development of molecules needed for the evaluation of the Hsp90 CTD as a target for the development of anticancer drugs.
Highlights
Cancer remains one of the leading causes of disease, mortality and economic loss worldwide [1].While there have been considerable improvements in treatment and survival times for patients suffering from a number of different types of cancer, there is still an urgent need to identify novel molecular targets, curative therapies and anticancer agents with improved efficacy and reduced adverse outcomes [2,3]
The goals of the LB modeling study were threefold: (1) To address the important question of which chemical features a set of highly active Hsp90 C-terminal domain (CTD) inhibitors have in common in the 3D-space; (2) To utilize the LB model as a query to identify molecules with similar interaction patterns, and unique scaffolds via virtual screening (VS) of commercially available compounds; and (3) To compare the features of LB
Models based on a set of known Hsp90 CTD inhibitors, to SB models derived from molecular dynamics (MD) simulations, to make sense of interactions derived from a predicted allosteric binding site
Summary
Cancer remains one of the leading causes of disease, mortality and economic loss worldwide [1]. Hsp is a highly conserved molecular chaperone that is responsible for the folding, activation and maturation of more than 300 client proteins, including protein kinases, E3-ligases and transcription factors [4,5]. Since these Hsp clients are involved and play important roles in cancer, Hsp has been recognized as a promising target for development of anticancer drugs [6]. In contrast to Hsp NTD inhibitors, novobiocin did not induce theshock heat response after the treatment of cancer cells at concentrations needed for client protein degradation [17].
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