Identification of Isoform-Selective Ligands for the Middle Domain of Heat Shock Protein 90 (Hsp90)

The molecular chaperone heat shock protein 90 (Hsp90) is a current inhibition target for the treatment of diseases, including cancer. In humans, there are two major cytosolic isoforms of Hsp90 (Hsp90 alpha and Hsp90 beta). Hsp90 alpha is inducible and Hsp90 beta is constitutively expressed. Most Hsp90 inhibitors are pan-inhibitors that target both cytosolic isoforms of Hsp90. The development of isoform-selective inhibitors of Hsp90 may enable better clinical outcomes. Herein, by using virtual screening and binding studies, we report our work in the identification and characterisation of novel isoform-selective ligands for the middle domain of Hsp90 beta. Our results pave the way for further development of isoform-selective Hsp90 inhibitors.