Towards allosteric modulators of Hsp90

Hsp90 is an established anti-apoptotic target in cancer therapy.1 Most of the known small-molecule inhibitors that have shown potent antitumor activity target the Hsp90 N-terminal domain and directly inhibit its ATP-ase activity.2 However, many of these molecules display important secondary effects. A different approach to Hsp90 inhibition consists of targeting the protein C-terminal domain (CTD) and modulating its chaperone activity through allosteric effects. Using an original computational approach, allosteric hot-spots in the CTD have been recently identified that control interdomain communication.3 A combination of virtual and experimental screening enabled identification of 1 (Eupomatenoid-2, Figure 1) as a lead for further development.3 Four diversification areas have been identified (R1-R4, Figure 1).
Chemical approaches to the (glyco)diversification at R4 will be presented,4 along with alternative synthetic pathways for the synthesis of the 2-phenyl-benzofuran core and its diversification at R1.
Preliminary results indicate that the compounds obtained so far are CTD ligands and are able to modulate Hsp90 activity.