Cargando…
Evaluation of 3‐ and 4‐Phenoxybenzamides as Selective Inhibitors of the Mono‐ADP‐Ribosyltransferase PARP10
Intracellular ADP‐ribosyltransferases catalyze mono‐ and poly‐ADP‐ribosylation and affect a broad range of biological processes. The mono‐ADP‐ribosyltransferase PARP10 is involved in signaling and DNA repair. Previous studies identified OUL35 as a selective, cell permeable inhibitor of PARP10. We ha...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485830/ https://www.ncbi.nlm.nih.gov/pubmed/34145784 http://dx.doi.org/10.1002/open.202100087 |
_version_ | 1784577612989857792 |
---|---|
author | Korn, Patricia Classen, Arno Murthy, Sudarshan Guareschi, Riccardo Maksimainen, Mirko M. Lippok, Barbara E. Galera‐Prat, Albert Sowa, Sven T. Voigt, Catharina Rossetti, Giulia Lehtiö, Lari Bolm, Carsten Lüscher, Bernhard |
author_facet | Korn, Patricia Classen, Arno Murthy, Sudarshan Guareschi, Riccardo Maksimainen, Mirko M. Lippok, Barbara E. Galera‐Prat, Albert Sowa, Sven T. Voigt, Catharina Rossetti, Giulia Lehtiö, Lari Bolm, Carsten Lüscher, Bernhard |
author_sort | Korn, Patricia |
collection | PubMed |
description | Intracellular ADP‐ribosyltransferases catalyze mono‐ and poly‐ADP‐ribosylation and affect a broad range of biological processes. The mono‐ADP‐ribosyltransferase PARP10 is involved in signaling and DNA repair. Previous studies identified OUL35 as a selective, cell permeable inhibitor of PARP10. We have further explored the chemical space of OUL35 by synthesizing and investigating structurally related analogs. Key synthetic steps were metal‐catalyzed cross‐couplings and functional group modifications. We identified 4‐(4‐cyanophenoxy)benzamide and 3‐(4‐carbamoylphenoxy)benzamide as PARP10 inhibitors with distinct selectivities. Both compounds were cell permeable and interfered with PARP10 toxicity. Moreover, both revealed some inhibition of PARP2 but not PARP1, unlike clinically used PARP inhibitors, which typically inhibit both enzymes. Using crystallography and molecular modeling the binding of the compounds to different ADP‐ribosyltransferases was explored regarding selectivity. Together, these studies define additional compounds that interfere with PARP10 function and thus expand our repertoire of inhibitors to further optimize selectivity and potency. |
format | Online Article Text |
id | pubmed-8485830 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-84858302021-10-06 Evaluation of 3‐ and 4‐Phenoxybenzamides as Selective Inhibitors of the Mono‐ADP‐Ribosyltransferase PARP10 Korn, Patricia Classen, Arno Murthy, Sudarshan Guareschi, Riccardo Maksimainen, Mirko M. Lippok, Barbara E. Galera‐Prat, Albert Sowa, Sven T. Voigt, Catharina Rossetti, Giulia Lehtiö, Lari Bolm, Carsten Lüscher, Bernhard ChemistryOpen Full Papers Intracellular ADP‐ribosyltransferases catalyze mono‐ and poly‐ADP‐ribosylation and affect a broad range of biological processes. The mono‐ADP‐ribosyltransferase PARP10 is involved in signaling and DNA repair. Previous studies identified OUL35 as a selective, cell permeable inhibitor of PARP10. We have further explored the chemical space of OUL35 by synthesizing and investigating structurally related analogs. Key synthetic steps were metal‐catalyzed cross‐couplings and functional group modifications. We identified 4‐(4‐cyanophenoxy)benzamide and 3‐(4‐carbamoylphenoxy)benzamide as PARP10 inhibitors with distinct selectivities. Both compounds were cell permeable and interfered with PARP10 toxicity. Moreover, both revealed some inhibition of PARP2 but not PARP1, unlike clinically used PARP inhibitors, which typically inhibit both enzymes. Using crystallography and molecular modeling the binding of the compounds to different ADP‐ribosyltransferases was explored regarding selectivity. Together, these studies define additional compounds that interfere with PARP10 function and thus expand our repertoire of inhibitors to further optimize selectivity and potency. John Wiley and Sons Inc. 2021-06-19 /pmc/articles/PMC8485830/ /pubmed/34145784 http://dx.doi.org/10.1002/open.202100087 Text en © 2021 The Authors. Published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Full Papers Korn, Patricia Classen, Arno Murthy, Sudarshan Guareschi, Riccardo Maksimainen, Mirko M. Lippok, Barbara E. Galera‐Prat, Albert Sowa, Sven T. Voigt, Catharina Rossetti, Giulia Lehtiö, Lari Bolm, Carsten Lüscher, Bernhard Evaluation of 3‐ and 4‐Phenoxybenzamides as Selective Inhibitors of the Mono‐ADP‐Ribosyltransferase PARP10 |
title | Evaluation of 3‐ and 4‐Phenoxybenzamides as Selective Inhibitors of the Mono‐ADP‐Ribosyltransferase PARP10 |
title_full | Evaluation of 3‐ and 4‐Phenoxybenzamides as Selective Inhibitors of the Mono‐ADP‐Ribosyltransferase PARP10 |
title_fullStr | Evaluation of 3‐ and 4‐Phenoxybenzamides as Selective Inhibitors of the Mono‐ADP‐Ribosyltransferase PARP10 |
title_full_unstemmed | Evaluation of 3‐ and 4‐Phenoxybenzamides as Selective Inhibitors of the Mono‐ADP‐Ribosyltransferase PARP10 |
title_short | Evaluation of 3‐ and 4‐Phenoxybenzamides as Selective Inhibitors of the Mono‐ADP‐Ribosyltransferase PARP10 |
title_sort | evaluation of 3‐ and 4‐phenoxybenzamides as selective inhibitors of the mono‐adp‐ribosyltransferase parp10 |
topic | Full Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485830/ https://www.ncbi.nlm.nih.gov/pubmed/34145784 http://dx.doi.org/10.1002/open.202100087 |
work_keys_str_mv | AT kornpatricia evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT classenarno evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT murthysudarshan evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT guareschiriccardo evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT maksimainenmirkom evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT lippokbarbarae evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT galerapratalbert evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT sowasvent evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT voigtcatharina evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT rossettigiulia evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT lehtiolari evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT bolmcarsten evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 AT luscherbernhard evaluationof3and4phenoxybenzamidesasselectiveinhibitorsofthemonoadpribosyltransferaseparp10 |