High expression levels of the molecular chaperone HSP70 have been linked to poor prognosis in cancer.1 Despite significant research effort, targeting HSP70 has proved challenging due to its flexible structure and complex catalytic cycle. Most published inhibitors have poorly characterised modes of action and only moderate to weak potency.2Fluorescence Polarisation (FP) and Surface Plasmon Resonance (SPR) techniques were used to elucidate the mechanisms of action of reported HSP70 inhibitors, apoptozole3-4 and VER-1550085(Figure 1). Fluorescent probes derived from the inhibitors were designed and synthesised using new synthetic routes amenable to analogue synthesis and fluorophore attachment. An FP assay was established and used to interrogate interactions between the inhibitors and HSP70 or HSP70/co-chaperone complexes. Finally, a screen for small molecule inhibitors targeting a novel HSP70 complex was established.Figure 1  a. Structure of HSP70 inhibitors apoptozole and VER-155008; b. X-Ray crystal structure of VER-155008 (pink) bound to HSP70 (green) in complex with co-chaperone BAG1 (blue), PDB: 3FZM.2Powers, M. V.; Jones, K.; Barillari, C.; Westwood, I.; van Montfort, R. L. M.; Workman, P. Cell Cycle 2010  , 9, 1542.Massey, A. J. J. Med. Chem. 2010  , 53, 7280Williams, D. R.; Ko, S.-K.; Park, S.; Lee, M.-R.; Shin, I. Angew. Chem. Int. Ed. 2008  , 47, 7466.Cho, H. J.; Gee, H. Y.; Baek, K.-H.; Ko, S.-K.; Park, J.-M.; Lee, H.; Kim, N.-D.; Lee, M. G.; Shin, I. JACS 2011  , 133, 20267.Williamson, D. S.; Borgognoni, J.; Clay, A.; Daniels, Z.; Dokurno, P.; Drysdale, M. J.; Foloppe N.; Francis, G. L.; Graham, C. J.; Howes, R.; Macias, A. T.; Murray, J. B.; Parsons, R.; Shaw, T.; Surgenor, A. E.; Terry, L.; Wang, Y.; Wood, M.; Massey, A. J. J. Med. Chem. 2009  , 52, 1510.

Alternative strategies for targeting HSP70

248th National Meeting (2014)

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