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3 results on '"Korn, P. (Patricia)"'

1. [1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes

Author

Murthy, S. (Sudarshan), Nizi, M. G. (Maria Giulia), Maksimainen, M. M. (Mirko M.), Massari, S. (Serena), Alaviuhkola, J. (Juho), Lippok, B. E. (Barbara E.), Vagaggini, C. (Chiara), Sowa, S. T. (Sven T.), Galera-Prat, A. (Albert), Ashok, Y. (Yashwanth), Venkannagari, H. (Harikanth), Prunskaite-Hyyryläinen, R. (Renata), Dreassi, E. (Elena), Lüscher, B. (Bernhard), Korn, P. (Patricia), Tabarrini, O. (Oriana), Lehtiö, L. (Lari), Murthy, S. (Sudarshan), Nizi, M. G. (Maria Giulia), Maksimainen, M. M. (Mirko M.), Massari, S. (Serena), Alaviuhkola, J. (Juho), Lippok, B. E. (Barbara E.), Vagaggini, C. (Chiara), Sowa, S. T. (Sven T.), Galera-Prat, A. (Albert), Ashok, Y. (Yashwanth), Venkannagari, H. (Harikanth), Prunskaite-Hyyryläinen, R. (Renata), Dreassi, E. (Elena), Lüscher, B. (Bernhard), Korn, P. (Patricia), Tabarrini, O. (Oriana), and Lehtiö, L. (Lari)

Abstract

We report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogues and cocrystal structures with TNKS2, PARP2, PARP14, and PARP15. Based on the substitution pattern, we were able to identify 3-amino derivatives 21 (OUL243) and 27 (OUL232) as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14, and PARP15 at nM potencies, with 27 being the most potent PARP10 inhibitor described to date (IC50 of 7.8 nM) and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity toward PARP2. The scaffold does not possess inherent cell toxicity, and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of TBT scaffold for future drug development efforts toward selective inhibitors against specific enzymes.

Published
2023

2. Evaluation of 3- and 4-phenoxybenzamides as selective inhibitors of the Mono-ADP ribosyltransferase PARP10

Author

Korn, P. (Patricia), Classen, A. (Arno), Murthy, S. (Sudarshan), Guareschi, R. (Riccardo), Maksimainen, M. M. (Mirko M.), Lippok, B. E. (Barbara E.), Galera-Prat, A. (Albert), Sowa, S. T. (Sven T.), Voigt, C. (Catharina), Rossetti, G. (Giulia), Lehtiö, L. (Lari), Bolm, C. (Carsten), and Lüscher, B. (Bernhard)

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

Published
2021

3. ADP-ribosyltransferases, an update on function and nomenclature

Author

Lüscher, B. (Bernhard), Ahel, I. (Ivan), Altmeyer, M. (Matthias), Ashworth, A. (Alan), Bai, P. (Peter), Chang, P. (Paul), Cohen, M. (Michael), Corda, D. (Daniela), Dantzer, F. (Françoise), Daugherty, M. D. (Matthew D.), Dawson, T. M. (Ted M.), Dawson, V. L. (Valina L.), Deindl, S. (Sebastian), Fehr, A. R. (Anthony R.), Feijs, K. L. (Karla L. H.), Filippov, D. V. (Dmitri V.), Gagné, J.-P. (Jean-Philippe), Grimaldi, G. (Giovanna), Guettler, S. (Sebastian), Hoch, N. C. (Nicolas C.), Hottiger, M. O. (Michael O.), Korn, P. (Patricia), Kraus, W. L. (W. Lee), Ladurner, A. (Andreas), Lehtiö, L. (Lari), Leung, A. K. (Anthony K. L.), Lord, C. J. (Christopher J.), Mangerich, A. (Aswin), Matic, I. (Ivan), Matthews, J. (Jason), Moldovan, G.-L. (George-Lucian), Moss, J. (Joel), Natoli, G. (Gioacchino), Nielsen, M. L. (Michael L.), Niepel, M. (Mario), Nolte, F. (Friedrich), Pascal, J. (John), Paschal, B. M. (Bryce M.), Pawłowski, K. (Krzysztof), Poirier, G. G. (Guy G.), Smith, S. (Susan), Timinszky, G. (Gyula), Wang, Z.-Q. (Zhao-Qi), Yélamos, J. (José), Yu, X. (Xiaochun), Zaja, R. (Roko), Ziegler, M. (Mathias), Lüscher, B. (Bernhard), Ahel, I. (Ivan), Altmeyer, M. (Matthias), Ashworth, A. (Alan), Bai, P. (Peter), Chang, P. (Paul), Cohen, M. (Michael), Corda, D. (Daniela), Dantzer, F. (Françoise), Daugherty, M. D. (Matthew D.), Dawson, T. M. (Ted M.), Dawson, V. L. (Valina L.), Deindl, S. (Sebastian), Fehr, A. R. (Anthony R.), Feijs, K. L. (Karla L. H.), Filippov, D. V. (Dmitri V.), Gagné, J.-P. (Jean-Philippe), Grimaldi, G. (Giovanna), Guettler, S. (Sebastian), Hoch, N. C. (Nicolas C.), Hottiger, M. O. (Michael O.), Korn, P. (Patricia), Kraus, W. L. (W. Lee), Ladurner, A. (Andreas), Lehtiö, L. (Lari), Leung, A. K. (Anthony K. L.), Lord, C. J. (Christopher J.), Mangerich, A. (Aswin), Matic, I. (Ivan), Matthews, J. (Jason), Moldovan, G.-L. (George-Lucian), Moss, J. (Joel), Natoli, G. (Gioacchino), Nielsen, M. L. (Michael L.), Niepel, M. (Mario), Nolte, F. (Friedrich), Pascal, J. (John), Paschal, B. M. (Bryce M.), Pawłowski, K. (Krzysztof), Poirier, G. G. (Guy G.), Smith, S. (Susan), Timinszky, G. (Gyula), Wang, Z.-Q. (Zhao-Qi), Yélamos, J. (José), Yu, X. (Xiaochun), Zaja, R. (Roko), and Ziegler, M. (Mathias)

Abstract

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD⁺ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.

Published
2021

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