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

Article


Allardyce, D., Adu Mantey, P., Szalecka, M., Nkwo, R. and Loizidou, E. 2023. Identification of a new class of proteasome inhibitors based on a naphthyl-azotricyclic-urea-phenyl scaffold. RSC Medicinal Chemistry. 14 (3), pp. 573-582. https://doi.org/10.1039/D2MD00404F
TypeArticle
TitleIdentification of a new class of proteasome inhibitors based on a naphthyl-azotricyclic-urea-phenyl scaffold
AuthorsAllardyce, D., Adu Mantey, P., Szalecka, M., Nkwo, R. and Loizidou, E.
Abstract

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.

Sustainable Development Goals3 Good health and well-being
Middlesex University ThemeHealth & Wellbeing
PublisherRoyal Society of Chemistry
JournalRSC Medicinal Chemistry
ISSN
Electronic2632-8682
Publication dates
Online06 Feb 2023
Print22 Mar 2023
Publication process dates
Deposited07 Feb 2023
Submitted04 Nov 2022
Accepted06 Feb 2023
Output statusPublished
Accepted author manuscript
Copyright Statement

This author's accepted manuscript version is included in this repository in accordance with the publisher's Green open access policy (https://www.rsc.org/journals-books-databases/open-access-publishing/...)

Digital Object Identifier (DOI)https://doi.org/10.1039/D2MD00404F
Web of Science identifierWOS:000934246500001
LanguageEnglish
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