Combined pharmacophore and structure-guided studies to identify diverse HSP90 inhibitors
Introduction
Heat Shock Protein 90 (HSP90), a 90-kDa chaperone, is highly conserved and ubiquitously expressed in all living organisms. It is an attractive molecular target because of its requirement for the stability and function of multiple mutated, chimeric and over-expressed signaling proteins that promote the growth and/or survival of cancer cells. HSP90 performs a key function by maintaining the proper folding conformation of various “client proteins”, and inhibition of HSP90 results in misfolded client proteins which are then rapidly degraded by the proteasome [1]. The HSP90 client proteins include many oncogenic signaling proteins such as ZAP-70, Her2/ErbB2, Akt, Raf-1, Hif-1a, hormone receptors, survivin, mutant p53, and hTERT [2]. Their role in the folding and maturation of various client proteins, as well as the rematuration of misfolded proteins, makes them potential targets for many diseases ranging from the disruption of multiple signaling pathways associated with cancer [2], [3] to the clearance of protein aggregates in neurodegenerative diseases [4]. Current HSP90 inhibitors are categorized into several classes based on distinct modes of inhibition like (i) blockade of ATP binding, (ii) disruption of co-chaperone/HSP90 interactions, (iii) antagonism of client/HSP90 associations and (iv) interference with post-translational modifications of HSP90 [5]. The ATPase activity of HSP90 drives the chaperone cycle and directs binding, induction of the active conformation and release of its client proteins. The majority of HSP90 inhibitors developed so far inhibit HSP90 ATPase activity by docking to the N-terminal ATP-binding pocket. This class of HSP90 inhibitors includes natural products Geldanamycin (GA), GA derivatives such as 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) and Radicicol [6]. Despite the good activity and clinical progression of 17-AAG, which is being studied in various clinical trials, this molecule has several potential limitations including poor solubility, limited bioavailability, hepatotoxicity and extensive metabolism by polymorphic enzymes [7]. Recently, three synthetic HSP90 inhibitors, with improved pharmacologic profile, have been developed with diverse chemical scaffolds [8]. These inhibitors are being studied for range of cancers in different clinical trials. Currently there are 26 clinical trials, ranging from phase 1 to 3, on 11 HSP90 inhibitors (both 17-AAG derivatives and synthetic inhibitors) for various indications like breast cancer, CLL, GI tumors, multiple myeloma, pancreatic cancer and other solid tumors (Supplementary Table 3). Out of the 11 HSP90 inhibitors which are in clinical evaluation, three synthetic small-molecule inhibitors—the purine-scaffold HSP90 inhibitor CNF-2024/BIIB021, the isoxazole derivative VER-52296/NVP-AUY922, and the carbazol-4-one benzamide derivative SNX-5422, were considered in this study as they have improved pharmacologic profile when compared to 17-AAG [9], [10]. Pharmacophore and docking models were generated using the above three inhibitors, which was further used to discover novel HSP90 inhibitors in HSP90-over expressing SKBr3 cells.
Section snippets
Common pharmacophore hypotheses
Common feature pharmacophore hypotheses were generated using a set of three HSP90 inhibitors (1–3, Fig. 2). The structures and conformations of the three compounds were built within Catalyst (Accelrys, Inc.) [11]. The Poling algorithm implemented within Catalyst was used to generate conformations for all of the compounds. For each compound, possible diverse sets of conformations were generated over a 20 kcal/mol range using the BEST flexible conformation generation option available in Catalyst.
Design of HSP90 inhibitors
We utilized three synthetic small-molecule HSP90 inhibitors, currently in clinical evaluation, to generate common feature pharmacophore models. These models were then validated against a database of 87 known HSP90 inhibitors. The validated pharmacophore model was further used as search query to retrieve molecules with novel structural scaffolds and desired chemical features. The overall work flow of molecular modeling and biological assay to identify novel HSP90 inhibitors is schematically
Conclusions
Several structurally diverse compounds possessing growth inhibitory potency against HSP90 over expressing cancer cells were identified using pharmacophore, cluster analysis and docking studies. The pharmacophore and docking models were generated and validated utilizing a set of known HSP90 inhibitors. These compounds bearing amenable chemical and structural features are potential leads for drug design strategies targeting HSP90. In conclusion, it has been shown that, modification of typical
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