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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...

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Autores principales: 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
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
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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.
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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
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