University of Oulu

Sudarshan Murthy, Jenny Desantis, Patricia Verheugd, Mirko M. Maksimainen, Harikanth Venkannagari, Serena Massari, Yashwanth Ashok, Ezeogo Obaji, Yves Nkizinkinko, Bernhard Lüscher, Oriana Tabarrini, Lari Lehtiö, 4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10, European Journal of Medicinal Chemistry, Volume 156, 2018, Pages 93-102, ISSN 0223-5234, https://doi.org/10.1016/j.ejmech.2018.06.047

4-(phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10

Saved in:
Author: Murthy, Sudarshan1; Desantis, Jenny2; Verheugd, Patricia3;
Organizations: 1Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
2Department of Pharmaceutical Sciences, University of Perugia, 06123, Perugia, Italy
3Institute of Biochemistry and Molecular Biology, RWTH Aachen University, 52074, Aachen, Germany
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe201902256248
Language: English
Published: Elsevier, 2018
Publish Date: 2020-06-20
Description:

Abstract

Human Diphtheria toxin-like ADP-ribosyltranferases (ARTD) 10 is an enzyme carrying out mono-ADP-ribosylation of a range of cellular proteins and affecting their activities. It shuttles between cytoplasm and nucleus and influences signaling events in both compartments, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and S phase DNA repair. Furthermore, overexpression of ARTD10 induces cell death. We recently reported on the discovery of a hit compound, OUL35 (compound 1), with 330 nM potency and remarkable selectivity towards ARTD10 over other enzymes in the human protein family. Here we aimed at establishing a structure-activity relationship of the OUL35 scaffold, by evaluating an array of 4-phenoxybenzamide derivatives. By exploring modifications on the linker between the aromatic rings, we identified also a 4-(benzyloxy)benzamide derivative, compound 32, which is potent (IC50 = 230 nM) and selective, and like OUL35 was able to rescue HeLa cells from ARTD10-induced cell death. Evaluation of an enlarged series of derivatives produced detailed knowledge on the structural requirements for ARTD10 inhibition and allowed the discovery of further tool compounds with submicromolar cellular potency that will help in understanding the roles of ARTD10 in biological systems.

see all

Series: European journal of medicinal chemistry
ISSN: 0223-5234
ISSN-E: 0223-5234
ISSN-L: 0223-5234
Volume: 156
Pages: 93 - 102
DOI: 10.1016/j.ejmech.2018.06.047
OADOI: https://oadoi.org/10.1016/j.ejmech.2018.06.047
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
Funding: This work was funded by Sigrid Jusélius foundation, Biocenter Oulu, Jane and Aatos Erkko Foundation, Academy of Finland (grant no. 287063 and 294085 for LL), German Research Foundation DFG (LU466/16-1 to BL), start-up program of the Excellence Initiative of the RWTH Aachen University (StUpPD_119_13 to PV), and the START program of the Faculty of Medicine, RWTH Aachen University (117/15 to PV).
Academy of Finland Grant Number: 287063
294085
Detailed Information: 287063 (Academy of Finland Funding decision)
294085 (Academy of Finland Funding decision)
Copyright information: © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
  https://creativecommons.org/licenses/by-nc-nd/4.0/