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Evaluation of 3- and 4-phenoxybenzamides as selective inhibitors of the mono-ADP-ribosyltransferase PARP10

DOI: 10.1002/open.202100087 DOI Help

Authors: Patricia Korn (RWTH Aachen University) , Arno Classen (RWTH Aachen University) , Sudarshan Murthy (University of Oulu) , Riccardo Guareschi (Forschungszentrum Jülich) , Mirko M. Maksimainen (University of Oulu) , Barbara E. Lippok (RWTH Aachen University) , Albert Galera‐prat (University of Oulu) , Sven T. Sowa (University of Oulu) , Catharina Voigt (RWTH Aachen University) , Giulia Rossetti (Forschungszentrum Jülich; RWTH Aachen University) , Lari Lehtio (University of Oulu) , Carsten Bolm (RWTH Aachen University) , Bernhard Lüscher (RWTH Aachen University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistryopen , VOL 384

State: Published (Approved)
Published: June 2021
Diamond Proposal Number(s): 19951

Open Access Open Access

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.

Journal Keywords: ADP-ribosylation; cell proliferation; compound screening; DNA repair; molecular modeling

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 21/06/2021 13:49

Documents:
open.202100087.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Catalysis Chemistry Structural biology Organic Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)