Binding of Natural and Synthetic Inhibitors to Human Heat Shock Protein 90 and Their Clinical Application

Vilma Petrikaitė,Daumantas Matulis

doi:10.3390/medicina47080062

Abstract

This review describes the recent progress in the field of heat shock protein 90 (Hsp90) inhibitor design. Hsp90 is a heat shock protein with a molecular weight of approximately 90 kDa. Hsp90 is considered a good anticancer target because its inhibition leads to inactivation of its numerous client proteins participating in various signaling and other processes involved in cancer progression. Numerous Hsp90 inhibitors-leads currently tested in clinical trials are presented in this review. Furthermore, this review emphasizes the application of biophysical binding assays in the development of Hsp90 inhibitors. The binding of designed lead compounds to various Hsp90 constructs is measured by isothermal titration calorimetry and thermal shift assay. These assays provide a detailed energetic insight of the binding reaction, including the enthalpy, entropy, heat capacity, and the Gibbs free energy. A detailed description of the binding energetics helps to extend our knowledge of structure-activity relationships in the design of more potent inhibitors. The most active compounds are then tested for their absorption, distribution, metabolism, elimination, toxicity, and activity against cancer cell lines.

Highlights

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that plays an important role in protein regulation in cells
Hsp90 was found to be overexpressed in a wide range of tumors, and it became a target of interest in oncology
Some of Hsp90 inhibitors bind to the N-terminal domain at the active site of ATP-binding pocket while others bind to the C-terminal domain

Summary

Introduction

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that plays an important role in protein regulation in cells. There are two groups of inhibitors binding at the N-terminal domain designed based on natural compounds: geldanamycin and radicicol. Hsp inhibition was thoroughly studied based on geldanamycin binding to Hsp and discussed in [17, 18] This natural compound from ansamycin family was found to be a strong inhibitor of chaperone in vitro and in vivo, but it demonstrated undesired liver toxicity [19] and could not be developed further as an anticancer agent. This compound attracted more attention after it was revealed as a useful agent for combined therapy since it enhanced efficacy of other chemotherapeutic agents [22] Another natural product, radicicol, is a very strong Hsp inhibitor and competes with ATP binding in the N-terminal domain. Combined drug Alone or with bortezomib or gemcitabine hydrochloride – Alone or with trastuzumab or paclitaxel Alone or combined with erlotinib hydrochloride, capecitabine, trastuzumab or cetuximab – Alone or with imatinib – – –

Route Intravenous Intravenous Intravenous

Findings

Molar Ratio