Proteasome plays an important role in protein degradation and regulation of many cellular pathways and as such, is a significant target for the treatment of many diseases, including cancer. Clinically used inhibitors of the proteasome have shown great success in the treatment of multiple myeloma and mantle cell lymphoma but yet exhibit side effects and toxicity, rendering the discovery of new inhibitors with higher therapeutic index, a necessity. Virtual screening of a library of natural products (ZINC) led to the identification of a class of naphthyl carbonyl phenyl urea compounds as inhibitors of the β5 site of the proteasome. These compounds showed evidence of dose dependency though proteasome assays with IC50 values in the low micromolar range. The inhibition mode of 3-(3-cyanophenyl)-1-(2-naphthylcarbonyl-oxo-BLAHyl)-urea (ZINC4258888) was further analyzed at a range of substrate and inhibitor concentrations the results of which revealed competitive binding at the β5 site with an estimated inhibition constant, Ki 4μΜ. Molecular docking analysis of the binding mode of structural analogues identified the naphthyl and cyanophenyl groups to be important for activity. The results of this study led to the identification of a potentially new class of proteasome inhibitors that can be further optimised through structure-activity relationship studies.

Identification of a new class of proteasome inhibitors based on a naphthylcarbonyl-phenyl urea scaffold

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.