A druggable pocket on PSMD10 that can accommodate an interface peptide and doxorubicin.

BACKGROUND

PSMD10, a proteasomal chaperone is also an oncoprotein. Overexpression of PSMD10 is associated with poor prognosis and survival in many cancers. Therefore, PSMD10 is a sought-after drug target in many hard-to-treat cancers. However, its surface appears flat and undruggable. Here, we build on our earlier discovery of a common hot spot region that defined the interface of multiple interacting partners of PSMD10 to expose vulnerable spots for a peptide and a small molecule inhibitor.

METHODS

High throughput virtual screening was used to screen compounds against PSMD10. Interaction of PSMD10 with the drug or protein (CLIC1) or peptide was studied using any one or more of these techniques; Microscale Thermophoresis, limited trypsinolysis, SPR and ITC. Cytotoxic effect of doxorubicin was evaluated using MTT assay.

RESULTS

We identified doxorubicin as the first-generation small molecule inhibitor of PSMD10. K116 and to a lesser extent R41 on PSMD10 contribute to the bulk of binding energy for the peptide EEVD, CLIC1 and doxorubicin. We further demonstrate that PSMD10 is an intended target for doxorubicin in cells.

GENERAL SIGNIFICANCE

Drug design against protein interactions in general and PSMD10 in particular, remains a challenge. We provide consolidated biophysical evidence for the use of a shared interface motif EEVD as a possible inhibitor of interaction network in cancers driven by PSMD10. We identify a chemical scaffold for designing novel inhibitors of PSMD10. These findings will impact the field of protein interactions in the context of disease biology/drug discovery.