HSP90: Chaperone-me-not

Abstract

With increasing understanding of the molecular basis of carcinogenesis, its progression and metastasis, the cancer therapy has shifted from empirical approaches to targeting specific molecules that regulate the complex network of signalling pathways for cell survival and proliferation. These include key players in malignant transformation like protein kinases, transcription factors, steroid hormone receptors, cell cycle regulators, signal transduction proteins and regulators of apoptosis. Almost all these proteins depend upon the molecular chaperone Hsp90 for their proper folding, stability and function and thus are a part of the Hsp90 clientele. Dependence of these proteins on Hsp90 makes this chaperone an appealing target for cancer therapeutics. Inhibition of Hsp90 can affect multiple oncogenic pathways simultaneously. Moreover Hsp90 inhibitors selectively kill cancer cells compared to normal cells and cancer cells have greater dependence on Hsp90 for the maintenance of intracellular protein homeostasis. All this has led to a rapid pace discovery of Hsp90 clients as well as chemical inhibitors of Hsp90. The role of hsp90 in cancer, tumor selectivity of Hsp90 inhibitors and the current status of Hsp90 inhibitors are discussed in the present review.

The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells

“…So far, the strategy used to inhibit its chaperone activity has been to exploit molecules already used as HSP90 blockers. These compounds inhibit ATP binding at the HSP90 N-terminal domain (Figure 4) (99, 100) and are active on TRAP1 too, given the high similarity of its ATP-binding pocket with that of HSP90. The approach developed to increase the selectivity of these compounds for TRAP1 has been to link them to moieties that facilitate permeability across mitochondrial membranes and accumulation in the organelle.…”

Amberlyst‐15‐catalyzed Procedure for the Synthesis of Novel 2,4‐Dihydroxybenzoyl‐1,2,3‐triazoles and Molecular Modelling Studies for Hsp‐90 Inhibition

“…This protein has a crucial role in cell such that it is an ATP dependent molecular chaperone and helps in sustaining the stability and the proper conformations of protein. [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] In cancer cells, Hsp90 is over expressed and it aids in oncogenic development and survival of cancer cells. Because of this reason, Hsp90 has emerged as a promising area of cancer chemotherapy.…”

Use of NQO1 status as a selective biomarker for oesophageal squamous cell carcinomas with greater sensitivity to 17-AAG

“…HSP90 has been shown to be overexpressed in a number of cancers, and presents an attractive target for anti-cancer therapy, as it plays a central role in contributing to the maintenance of a number of the characteristic hallmarks of cancer cells, by chaperoning key proteins, and maintaining active conformations of signalling proteins, reviewed in [1]. These include important signalling proteins like EGFR and IGF1-R that have been implicated in sustaining the neoplastic phenotype in OSCC [2].…”