Hsp90 (Heat shock protein-90) is a chaperone protein and 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 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 areas of diversification were 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 ATPase and chaperone activity.

Synthesis of potential allosteric modulators of Hsp90 / S. Sattin, L. Morelli, M. Panza, G. Vettoretti, E. Moroni, G. Colombo, A. Bernardi. ((Intervento presentato al 10. convegno Spanish-Italian Symposium on Organic Chemistry tenutosi a Firenze nel 2014.

Synthesis of potential allosteric modulators of Hsp90

S. Sattin
Primo
;
L. Morelli
Secondo
;
A. Bernardi
Ultimo
2014

Abstract

Hsp90 (Heat shock protein-90) is a chaperone protein and 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 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 areas of diversification were 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 ATPase and chaperone activity.
Hsp90; allosteric modulation
Settore CHIM/06 - Chimica Organica
Synthesis of potential allosteric modulators of Hsp90 / S. Sattin, L. Morelli, M. Panza, G. Vettoretti, E. Moroni, G. Colombo, A. Bernardi. ((Intervento presentato al 10. convegno Spanish-Italian Symposium on Organic Chemistry tenutosi a Firenze nel 2014.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/249595
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