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

Proteasomes play an important role in protein degradation and regulation of many cellular pathways by maintaining protein balance. Inhibitors of the proteasome disrupt this balance affecting proteins that are key in malignancies and as such have found applications in the treatment of multiple myeloma and mantle cell lymphoma. However, resistance mechanisms have been reported for these proteasome inhibitors including mutations at the β5 site which necessitates the constant development of new inhibitors. In this work, we report the identification of a new class of proteasome inhibitors, polycyclic molecules bearing a naphtyl-azotricyclic-urea phenyl scaffold, from screening of the ZINC library of natural products. The most potent of these compounds showed evidence of dose dependency though proteasome assays with IC50 values in the low micromolar range and kinetic analysis revealed competitive binding at the β5c site with an estimated inhibition constant, Ki 1.15μΜ. Inhibition was also shown for the β5i site of the immunoproteasome at levels similar to the constitutive proteasome. Structure activity relationship studies identified the naphthyl substituent to be crucial for activity and modelling studies attributed this to enhanced hydrophobic interactions within β5c. Further to this, halogen substitution within the naphthyl ring enhanced activity and allowed for π-π interactions with Y169 in β5c and Y130 and F124 in β5i. Combined these data highlight the importance of hydrophobic and halogen interactions in β5 binding and assist in the design of next generation inhibitors of the proteasome.

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