Allosteric modulators of Hsp90: design, synthesis and activity evaluation

Hsp90 is a molecular chaperone playing a pivotal role in the cell life cycle, an established anti-apoptotic target in cancer therapy[1] and a promising target for neurodegenerative diseases.[2] Hsp90 internal dynamics, crucial for its function, are strongly ATP-regulated and current pharmacological approaches block the chaperone with ATP-competitive inhibitors, inducing non-negligible secondary effects. We recently demonstrated that the protein internal dynamics can be modulated, and in particular activated, in an allosteric fashion, targeting the protein C-terminal domain (CTD) with a family of 2-phenyl-benzofuran derivatives.[3,4] The allosteric site we recently identified[5] is mechanically connected to the distal orthosteric ATP-binding site (65 \uc5) and the small variations induced by binding of the majority of our allosteric modulators produce significant variations of the protein overall dynamics, which translate macroscopically into an acceleration of the chaperone ATPase rate. Analysis of protein responses to first-generation activators was exploited to guide the design of novel derivatives with improved ability to stimulate ATP hydrolysis and protein closure kinetics.[6] The expansion of the initial library with 28 new derivatives that explore the chemical space at opposite ends of the benzofuran scaffold will be described. Their interaction with the full-length protein by STD-NMR and their effect on Hsp90 enzymatic, conformational, co-chaperone and client-binding properties will be also presented. Figure 1: A) Structure of a representative allosteric modulator and B) its docked conformation within the allosteric site. References 1) Trepel, J.; Mollapour, M.; Giaccone, G.et al, Nat Rev Cancer 2010, 10, 537-549. 2) Uversky, V. N., Chem. Rev. 2010, 111, 1134-1166. 3) Morelli, L.; Bernardi, A. and Sattin, S., Carbohydr Res 2014, 390C, 33-41. 4) Sattin, S.; Tao, J.; Vettoretti, G.et al, Chem. Eur. J. 2015, 21, 13598-13608. 5) Morra, G.; Neves, M. A. C.; Plescia, C. J.et al, J. Chem. Theory Comput. 2010, 6, 2978-2989. 6) Vettoretti, G.; Moroni, E.; Sattin, S.et al, Sci Rep 2016, accepted DOI: 10.1038/srep23830