Mechanism-based Drug Discovery. (360G-Wellcome-102358_Z_13_Z)

The Hsp70 proteins are a family of molecular chaperones required for correct protein folding in response to cellular stress. Hsp70 is up-regulated in numerous cancer types,and both RNAi silencing and pharmacological inhibition has been shown to induce cell death in transf ormed cells. As a result,extensive efforts have been made to develop an Hsp70 inhibitor. Several inhibitors have been reported,however all possess poor drug-like properties and for most their mechanism of action remains poorly understood. The aim of this study is to characterise these inhibitors,by their comparison using a suite of biochemical and biophysical assays. Dependent on the outcome of these studies, selected compounds will be further investigated using structural studies.