Synthetic Small Molecule Modulators of Hsp70 and Hsp40 Chaperones as Promising Anticancer Agents

Abstract

A class of chaperones dubbed heat shock protein 70 (Hsp70) possesses high relevance in cancer diseases due to its cooperative activity with the well-established anticancer target Hsp90. However, Hsp70 is closely connected with a smaller heat shock protein, Hsp40, forming a formidable Hsp70-Hsp40 axis in various cancers, which serves as a suitable target for anticancer drug design. This review summarizes the current state and the recent developments in the field of (semi-)synthetic small molecule inhibitors directed against Hsp70 and Hsp40. The medicinal chemistry and anticancer potential of pertinent inhibitors are discussed. Since Hsp90 inhibitors have entered clinical trials but have exhibited severe adverse effects and drug resistance formation, potent Hsp70 and Hsp40 inhibitors may play a significant role in overcoming the drawbacks of Hsp90 inhibitors and other approved anticancer drugs.

Keywords: Hsp40; Hsp70; anticancer agents; heat shock proteins.

Figure 1

Structures of NBD-binding and interfering compounds 1–8.

Figure 2

Structures of SBD-interacting Hsp70 inhibitors 9–11.

Figure 3

Structures of Grp78 inhibitors 12–22. *: chiral center or asymmetric carbon atom.

Figure 4

Structures of mortalin inhibitors 3b, 3c, 23–25.

Figure 5

Structures of Hsp40 modulators 26–35. *: chiral center or asymmetric carbon atom.

Figure 6

Cellular effects of Hsp70 isoforms and their inhibition by synthetic small molecules. Hsp70 is composed of two distinct domains, a 40 kDa N-terminal nucleotide-binding domain (NBD) that regulates client association and a 25 kDa C-terminal substrate-binding domain (SBD). Hsp70 is found in the cytosol with multicellular functions. Together with Hsp90 it acts as a multi-chaperone complex to modulate heat stress responses. Organelle-specific Hsp70 isoforms such as Grp78 in the endoplasmic reticulum or mortalin in mitochondria were identified as promising anticancer drug targets. Inhibition of these multicellular processes by (semi-)synthetic inhibitors (red lines) leads to cell senescence, apoptosis and cell cycle arrest in various cancers.