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Evaluation of 3- and 4-Phenoxybenzamides as Selective Inhibitors of the Mono-ADP-Ribosyltransferase PARP10 |
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| Authors: | Dr. Patricia Korn Arno Classen Dr. Sudarshan Murthy Dr. Riccardo Guareschi Mirko M. Maksimainen Barbara E. Lippok Albert Galera-Prat Sven T. Sowa Catharina Voigt Prof. Dr. Giulia Rossetti Prof. Dr. Lari Lehtiö Prof. Dr. Carsten Bolm Prof. Dr. Bernhard Lüscher |
| Affiliation: | 1. Institute of Biochemistry and Molecular Biology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany These authors contributed equally to this work.;2. Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany These authors contributed equally to this work.;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 These authors contributed equally to this work.;5. Institute of Biochemistry and Molecular Biology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany;6. 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;7. Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany |
| 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 cell proliferation compound screening DNA repair molecular modeling |