P. Korn, A. Classen, S. Murthy, R. Guareschi, M. M. Maksimainen, B. E. Lippok, A. Galera-Prat, S. T. Sowa, C. Voigt, G. Rossetti, L. Lehtiö, C. Bolm, B. Lüscher, ChemistryOpen 2021, 10, 939, https://doi.org/10.1002/open.202100087
Evaluation of 3- and 4-phenoxybenzamides as selective inhibitors of the Mono-ADP ribosyltransferase PARP10
|Author:||Korn, Patricia1; Classen, Arno2; Murthy, Sudarshan3;|
1Institute of Biochemistry and Molecular Biology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
2Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
3Faculty of Biochemistry and Molecular Medicine & Biocenter Oulo, University of Oulu, Pentti Kaiteran katu 1, 90014 Oulu, Finland
4Institute for Advanced Simulation (IAS-5)/Institute of Neuroscience and Medicine (INM-9), Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, Wilhelm-Johnen-Strasse, 52425 Jülich, Germany
5Juelich Supercomputing Center (JSC), Forschungszentrum Jülich, Wilhelm-Johnen-Strasse, 52425 Jülich, Germany
6Department of Oncology, Hematology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
|Online Access:||PDF Full Text (PDF, 1.4 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2021121761478
John Wiley & Sons,
|Publish Date:|| 2021-12-17
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.
|Pages:||939 - 948|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
The work was supported by the Deutsche Forschungsgemeinschaft to BL (Lu 466/16-1 and 466/16-2), by the RWTH Aachen University program on Multiscale Biology to PK, GR, CB, and BL ( MSCALE013), by the Academy of Finland (grant no. 287063 and 294085) and by Sigrid Jusélius and Jane and Aatos Erkko foundations to LL.
© 2021 The Authors. Published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.