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Review
. 2010;10(14):1380-402.
doi: 10.2174/156802610792232088.

Macrocyclic inhibitors of hsp90

Victoria A Johnson  1 , Erinprit K Singh, Lidia A Nazarova, Leslie D Alexander, Shelli R McAlpine
Affiliations
Review

Macrocyclic inhibitors of hsp90

Victoria A Johnson et al. Curr Top Med Chem. 2010.

Abstract

Heat shock proteins (HSP) are a family of highly conserved proteins, whose expression increases in response to stresses that may threaten cell survival. Over the past decade, heat shock protein 90 (Hsp90) has emerged as a potential therapeutic target for cancer as it plays a vital role in normal cell maturation and acts as a molecular chaperone for proper folding, assembly, and stabilization of many oncogenic proteins. To date, a majority of Hsp90 inhibitors that have been discovered are macrocycles. The relatively rigid conformation provided by the macrocyclic scaffold allows for a selective interaction with a biological target such as Hsp90. This review highlights the discovery and development of nine macrocycles that inhibit the function of Hsp90, detailing their potency and the client proteins affected by Hsp90 inhibition.

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Figures

Fig. 1
Fig. 1
Hsp90 and its associated oncogenic client proteins.
Fig. 2
Fig. 2
Hsp90 cycle.
Fig. 3
Fig. 3
Natural trans amide structure of Geldanamycin.
Fig. 4
Fig. 4
Cis-amide conformation of Geldanamycin and the major interactions occurring in the N-terminal ATP-binding pocket of Hsp90.
Fig. 5
Fig. 5
Derivatives synthesized by Schnur and co-workers.
Fig. 6
Fig. 6
Simplified versions of GA.
Fig. 7
Fig. 7
GA derivatives with modifications at C-11.
Fig. 8
Fig. 8
GA derivatives with modifications at C-17
Fig. 9
Fig. 9
Structure of 17-AAG.
Fig. 10
Fig. 10
The cell cycle: Hsp90 client proteins required at G1 and G2 checkpoint are shown.
Fig. 11
Fig. 11
Structure of 17-AAG compared to 17-AG.
Fig. 12
Fig. 12
Structure of 17-DMAG.
Fig. 13
Fig. 13
Structure of 17-AAG and IPI-504.
Fig. 14
Fig. 14
Structures of Geldanamycin and Herbimycin.
Fig. 15
Fig. 15
Synthetic modifications to HA.
Fig. 16
Fig. 16
Potent HA derivative.
Fig. 17
Fig. 17
Synthetic modifications to HA incorporating halogens.
Fig. 18
Fig. 18
Structure of Radicicol.
Fig. 19
Fig. 19
Geldanamycin and Radicicol interactions with the N-terminal binding site of Hsp90.
Fig. 20
Fig. 20
Structures of KF25706 and KF2711.
Fig. 21
Fig. 21
Most potent carbamoylmethyl group
Fig. 22
Fig. 22
Structures of KF58333 and KF58332.
Fig. 23
Fig. 23
Structures of Radicicol, Pochonin D, E, and additional derivatives.
Fig. 24
Fig. 24
Structure of Radanamycin.
Fig. 25
Fig. 25
Structures of macrocyclic peptides Sansalvamide A and Di-Sansalvamide A.
Fig. 26
Fig. 26
San A binds to NM domain and Di-San A binds to MC domain, inducing apoptosis.
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