Inhibitors and chemical probes for molecular chaperone networks

Abstract

The molecular chaperones are central mediators of protein homeostasis. In that role, they engage in widespread protein-protein interactions (PPIs) with each other and with their "client" proteins. Together, these PPIs form the backbone of a network that ensures proper vigilance over the processes of protein folding, trafficking, quality control, and degradation. The core chaperones, such as the heat shock proteins Hsp60, Hsp70, and Hsp90, are widely expressed in most tissues, yet there is growing evidence that the PPIs among them may be re-wired in disease conditions. This possibility suggests that these PPIs, and perhaps not the individual chaperones themselves, could be compelling drug targets. Indeed, recent efforts have yielded small molecules that inhibit (or promote) a subset of inter-chaperone PPIs. These chemical probes are being used to study chaperone networks in a range of models, and the successes with these approaches have inspired a community-wide objective to produce inhibitors for a broader set of targets. In this Review, we discuss progress toward that goal and point out some of the challenges ahead.

Keywords: 70 kilodalton heat shock protein (Hsp70); chemical biology; drug discovery; heat shock protein 90 (Hsp90); high-throughput screening; inhibitor; molecular chaperone; protein folding; protein–protein interaction; proteostasis; small molecule inhibitor.

Figure 1.

Diversity of PPIs between molecular chaperones. Representative structures of PPIs between chaperones are shown. Hsp70 refers to the nucleotide-binding domain of either the prokaryotic or eukaryotic protein, and ACD is the α-crystallin domain of a small heat shock protein. Monomers of Hsp60 are shown in blue and orange. Please see the citations and PDB codes for information on the exact constructs used: Hsp70-J domain (5NRO); Hsp70–BAG (1HX1); TPR–EEVD (4KBQ); Hsp90–Aha1 (1USU); Hsp90–p23 (2CG9); Hsp90–Cdc37–Cdk4 (5FWP); Hsp60–Hsp10 (4PJ1); TRiC (5GW4); α-crystallin ACD–ACD (2WJ7); and Hsp27 ACD–IPV (4MJH).

Figure 2.

PPIs between chaperones and their binding partners. A, table of BSA and affinity values for PPIs between chaperones. B, categorization of PPIs based on BSA and affinity values. Based on retrospective analyses of PPI inhibitors, certain quadrants are comparatively easier (green), challenging (gray), or difficult (red) to inhibit with drug-like small molecules.

Figure 3.

Selected chemical probes for molecular chaperones. See text for citations and details.