Influence of allosteric Hsp90 ATPase activators on its chaperoning activity

Hsp90 is a molecular chaperone with a starring role in the cell life cycle1 and an established anti-apoptotic target in cancer therapy.2 The protein internal dynamics are regulated by ATP and are critical for its function. Hsp90 can be modulated in an allosteric fashion as we have recently demonstrated, targeting the protein C-terminal domain (CTD) with a family of 2-phenyl-benzofuran derivatives.3-5 These compounds accelerate Hsp90 internal dynamics and increase its enzymatic ATPase activity. As a result, they tune its chaperone activity in ways that we are just beginning to unravel. The synthetic approaches towards an expanded library of about 40 benzofuran derivatives will be presented. The interaction studies with full length Hsp90,6 and the effects on Hsp90 enzymatic and chaperoning activity will be reported for selected compounds. References 1. S. E. Jackson In Molecular Chaperones; Jackson, S., Ed.; Springer Berlin Heidelberg (2013) Vol. 328, p 155-240. 2. J. Trepel, M. Mollapour, G. Giaccone, and L. Neckers Nat Rev Cancer (2010), 10, 537-549. 3. L. Morelli, A. Bernardi and S. Sattin, Carbohydr. Res. (2014), 390, 33-41. 4. S. Sattin et al Chem. Eur. J. (2015), 21, 13598-13608. 5. G. Vettoretti, E. Moroni, S. Sattin, J. Tao, D.A. Agard, A. Bernardi and G. Colombo Sci Rep (2016), 6, 23830. 6. S. Sattin, M. Panza, F. Vasile, F. Berni, G. Goti, J. Tao, E. Moroni, D.A. Agard, G. Colombo and A. Bernardi Eur. J.Org. Chem. (2016) DOI: 10.1002/ejoc.201600420