2. Academic Validation
  3. Evaluation of 3- and 4-Phenoxybenzamides as Selective Inhibitors of the Mono-ADP-Ribosyltransferase PARP10

Evaluation of 3- and 4-Phenoxybenzamides as Selective Inhibitors of the Mono-ADP-Ribosyltransferase PARP10

  • ChemistryOpen. 2021 Oct;10(10):939-948. doi: 10.1002/open.202100087.
Patricia Korn 1,  Arno Classen 2,  Sudarshan Murthy 3,  Riccardo Guareschi 4,  Mirko M Maksimainen 3,  Barbara E Lippok 1,  Albert Galera-Prat 3,  Sven T Sowa 3,  Catharina Voigt 1,  Giulia Rossetti 4 5 6,  Lari Lehtiö 3,  Carsten Bolm 2,  Bernhard Lüscher 1
Affiliations

Affiliations

  • 1 Institute of Biochemistry and Molecular Biology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.
  • 2 Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056, Aachen, Germany.
  • 3 Faculty of Biochemistry and Molecular Medicine & Biocenter Oulo, University of Oulu, Pentti Kaiteran katu 1, 90014, Oulu, Finland.
  • 4 Institute for Advanced Simulation (IAS-5)/Institute of Neuroscience and Medicine (INM-9), Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, Wilhelm-Johnen-Strasse, 52425, Jülich, Germany.
  • 5 Juelich Supercomputing Center (JSC), Forschungszentrum Jülich, Wilhelm-Johnen-Strasse, 52425, Jülich, Germany.
  • 6 Department of Oncology, Hematology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.
PMID: 34145784 DOI: 10.1002/open.202100087
Abstract

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.

Keywords

ADP-ribosylation; DNA repair; cell proliferation; compound screening; molecular modeling.

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