Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

Abstract

Cancer cells survive in the presence of stresses that would normally cause cell death. To accomplish this feat, they express elevated levels of the molecular chaperones: heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90). Knockdown of these chaperones is selectively toxic to cancer cells, suggesting that they might be promising nodes for anticancer therapy. However, while inhibitors of Hsp90 are well known, progress in the development of Hsp70 inhibitors has proven more difficult. Hsp70 binds tightly to ATP through a highly conserved domain of the actin/hexokinase superfamily, making it challenging to identify selective, competitive inhibitors. Despite this obstacle, progress has been made and first-generation molecules are being deployed. To supplement these efforts, compounds that target important allosteric sites on the chaperone have also been discovered. In some of these cases, the molecules have been shown to control key protein-protein interactions between Hsp70 and its co-chaperones. In other cases, allosteric sites have been used to gain unexpected selectivity for members of the Hsp70 family. Here, we review recent progress in the development of Hsp70 inhibitors.

Insight into the Interaction of Cationic Porphyrin-Anthraquinone Hybrids with Hsp90: In Silico Analysis

“…Heat shock protein 90 (Hsp90) is a molecular chaperone that regulates the maturation, stabilization and activation of many cellular polypeptides important in cell growth, differentiation and survival. Client proteins of Hsp90 include tyrosine kinases, cell cycle regulators, and transcription factors, such as Akt, Raf-1, Her2, and Bcr-Abl [1,2]. In cancerous cells, the client proteins are involved in oncogenic processes ascribed to the ten well-defined hallmarks of cancer; this is confirmed by the fact that Hsp90 expression in the cancerous cells increases 2-3 fold compared to normal cells [3][4][5].…”

Combined In-Solution Fragment Screening and Crystallographic Binding-Mode Analysis with a Two-Domain Hsp70 Construct

“…15−17 Hsp70s are thereby assisted by cochaperones, namely, nucleotide exchange factors (NEFs), J-proteins, and tetratricopeptide repeat (TPR) domain-containing proteins. 18 Much effort was spent to develop molecules that either compete with the nucleotides or act in an allosteric manner, and various inhibitors have been described to inhibit or modulate the activity of Hsp70s. 19,20 Addressing the ATP site goes along with several problems, like pleiotropic effects and toxicity as well as affinities insufficient to displace nucleotides effectively due to the strong binding and high cellular concentrations of the latter.…”

“…Within this cycle, ATP binding and hydrolysis lead to large-scale conformational changes, including domain association and enhanced substrate binding and release in the ATP state, whereas the ADP state is characterized by rather independently behaving domains and a closed substrate-binding site with low substrate-exchange rates. Vice versa, substrate binding also stimulates ATP-turnover in the NBD. − Hsp70s are thereby assisted by cochaperones, namely, nucleotide exchange factors (NEFs), J-proteins, and tetratricopeptide repeat (TPR) domain-containing proteins …”

Designing de Novo Small Molecules That Control Heat Shock Protein 70 (Hsp70) and Heat Shock Organizing Protein (HOP) within the Chaperone Protein-Folding Machinery

“…Most inhibitors of Hsp70 act by competing for the ATP binding site or trapping Hsp70 in the ADP bound state. , To date, only one compound has been reported to target the Hsp70–HOP interaction, this compound acts via an allosteric mechanism and was rationally designed from an allosteric pocket with Hsp70s N-terminus . Herein we report the first design of molecules aimed to directly target the Hsp70–HOP interaction.…”