Synthesis and characterization of Hsp90 allosteric activators

Hsp90 is a molecular chaperone playing a pivotal 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. We have recently demonstrated that Hsp90 can be modulated in an allosteric fashion, targeting the protein C-terminal domain (CTD) with a family of 2-phenyl-benzofuran derivatives.3-5 These molecules increase Hsp90 ATPase rate and accelerate its internal dynamics. 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 diversified at positions R1 and R2 (Figure 1) will be presented together with the interaction studies with full length Hsp90.6 Figure 1: 2-phenyl-benzofuran diversification at positions R1 and R2. 1) Jackson, S. E. In Molecular Chaperones; Jackson, S., Ed.; Springer Berlin Heidelberg: 2013; Vol. 328, p 155-240. 2) Trepel, J.; Mollapour, M.; Giaccone, G. and Neckers, L., Nat Rev Cancer 2010, 10, 537-549. 3) Morelli, L.; Bernardi, A. and Sattin, S.*, Carbohydr. Res. 2014, 390, 33-41. 4) Sattin, S. et al Chem. Eur. J. 2015, 21, 13598-13608. 5) Vettoretti, G; Moroni, E.; Sattin, S.; Tao, J.; Agard, D. A.;. Bernardi, A. and Colombo, G. Sci Rep 2016, 6, 23830. 6) Sattin, S.*; Panza, M.; Vasile, F.; Berni, F.; Goti, G.; Tao, J.; Moroni, E.; Agard, D.; Colombo, G. and Bernardi, A. Eur. J.Org. Chem. 2016 DOI: 10.1002/ejoc.201600420.