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

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

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)93-102
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume156
DOIs
StatePublished - Aug 5 2018
Externally publishedYes

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Keywords

  • ADP-Ribosylation
  • ARTD
  • Inhibitor
  • PARP
  • Structure-activity relationship

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Murthy, S., Desantis, J., Verheugd, P., Maksimainen, M. M., Venkannagari, H., Massari, S., Ashok, Y., Obaji, E., Nkizinkinko, Y., Lüscher, B., Tabarrini, O., & Lehtiö, L. (2018). 4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10. European Journal of Medicinal Chemistry, 156, 93-102. https://doi.org/10.1016/j.ejmech.2018.06.047