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Review
. 2009 Mar 15;17(6):2225-35.
doi: 10.1016/j.bmc.2008.10.087. Epub 2008 Nov 6.

Discovery and development of heat shock protein 90 inhibitors

Tony Taldone  1 , Weilin Sun, Gabriela Chiosis
Affiliations
Review

Discovery and development of heat shock protein 90 inhibitors

Tony Taldone et al. Bioorg Med Chem. .

Abstract

Heat shock protein 90 (Hsp90) is an important target in cancer because of its role in maintaining transformation and has recently become the focus of several drug discovery and development efforts. While compounds with different modes of action are known, the focus of this review is on those classes of compounds which inhibit Hsp90 by binding to the N-terminal ATP pocket. These include natural product inhibitors such as geldanamycin and radicicol and synthetic inhibitors comprised of purines, pyrazoles, isoxazoles and other scaffolds. The synthetic inhibitors have been discovered either by structure-based design, high throughput screening and more recently using fragment-based design and virtual screening techniques. This review will discuss the discovery of these different classes, as well as their development as potential clinical agents.

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Figures

Figure 1
Figure 1
Structures of GM and related derivatives.
Figure 2
Figure 2
(A) GM (1) bound to yeast Hsp90 (1a4h.pdb). (B) RD (8) bound to yeast Hsp90 (1bgq.pdb). (C) PU3 (19) bound to human Hsp90 (1uym.pdb). (D) CCT018159 (35) bound to yeast Hsp90 (2brc.pdb).
Figure 3
Figure 3
Structures of RD and related derivatives.
Figure 4
Figure 4
Structures of chimeric molecules radamide and radester.
Figure 5
Figure 5
Structures of purine-scaffold Hsp90 inhibitors.
Figure 6
Figure 6
Benzothiazole, pyridinothiazole and N9-pyridylmethyl-substituted purine Hsp90 inhibitors.
Figure 7
Figure 7
Structure of pyrazole-scaffold Hsp90 inhibitors.
Figure 8
Figure 8
Structure of isoxazole-scaffold Hsp90 inhibitors.
Figure 9
Figure 9
Structures of some novel Hsp90 inhibitors.
See this image and copyright information in PMC

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