University of Oulu

Nizi, M. G., Maksimainen, M. M., Lehtiö, L., & Tabarrini, O. (2022). Medicinal chemistry perspective on targeting mono-adp-ribosylating parps with small molecules. Journal of Medicinal Chemistry, 65(11), 7532–7560.

Medicinal chemistry perspective on targeting mono-ADP-ribosylating PARPs with small molecules

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Author: Nizi, Maria Giulia1; Maksimainen, Mirko M.2; Lehtiö, Lari2;
Organizations: 1Department of Pharmaceutical Sciences, University of Perugia, 06123 Perugia, Italy
2Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 5400 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 11.3 MB)
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Language: English
Published: American Chemical Society, 2022
Publish Date: 2022-12-16


Major advances have recently defined functions for human mono-ADP-ribosylating PARP enzymes (mono-ARTs), also opening up potential applications for targeting them to treat diseases. Structural biology combined with medicinal chemistry has allowed the design of potent small molecule inhibitors which typically bind to the catalytic domain. Most of these inhibitors are at the early stages, but some have already a suitable profile to be used as chemical tools. One compound targeting PARP7 has even progressed to clinical trials. In this review, we collect inhibitors of mono-ARTs with a typical “H–Y−Φ” motif (Φ = hydrophobic residue) and focus on compounds that have been reported as active against one or a restricted number of enzymes. We discuss them from a medicinal chemistry point of view and include an analysis of the available crystal structures, allowing us to craft a pharmacophore model that lays the foundation for obtaining new potent and more specific inhibitors.

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Series: Journal of medicinal chemistry
ISSN: 0022-2623
ISSN-E: 1520-4804
ISSN-L: 0022-2623
Volume: 65
Issue: 11
Pages: 7532 - 7560
DOI: 10.1021/acs.jmedchem.2c00281
Type of Publication: A2 Review article in a scientific journal
Field of Science: 1182 Biochemistry, cell and molecular biology
Copyright information: © 2022 The Authors. Published by American Chemical Society.