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

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.

LanguageEnglish (US)
Pages93-102
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume156
DOIs
StatePublished - Aug 5 2018

Fingerprint

Proto-Oncogene Proteins
Benzamides
ADP Ribose Transferases
Poly(ADP-ribose) Polymerases
Enzyme Inhibitors
Cell death
Derivatives
Adenosine Diphosphate
Diphtheria Toxin
Biological systems
Enzymes
Scaffolds
Proteins
Repair
Cells
DNA

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10. / Murthy, Sudarshan; Desantis, Jenny; Verheugd, Patricia; Maksimainen, Mirko M.; Venkannagari, Harikanth; Massari, Serena; Ashok, Yashwanth; Obaji, Ezeogo; Nkizinkinko, Yves; Lüscher, Bernhard; Tabarrini, Oriana; Lehtiö, Lari.

In: European Journal of Medicinal Chemistry, Vol. 156, 05.08.2018, p. 93-102.

Research output: Contribution to journalArticle

Murthy, S, Desantis, J, Verheugd, P, Maksimainen, MM, 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, vol. 156, pp. 93-102. https://doi.org/10.1016/j.ejmech.2018.06.047
Murthy, Sudarshan ; Desantis, Jenny ; Verheugd, Patricia ; Maksimainen, Mirko M. ; Venkannagari, Harikanth ; Massari, Serena ; Ashok, Yashwanth ; Obaji, Ezeogo ; Nkizinkinko, Yves ; Lüscher, Bernhard ; Tabarrini, Oriana ; Lehtiö, Lari. / 4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10. In: European Journal of Medicinal Chemistry. 2018 ; Vol. 156. pp. 93-102.
@article{c89aa215c0504e79a146921359e975bb,
title = "4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10",
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.",
keywords = "ADP-Ribosylation, ARTD, Inhibitor, PARP, Structure-activity relationship",
author = "Sudarshan Murthy and Jenny Desantis and Patricia Verheugd and Maksimainen, {Mirko M.} and Harikanth Venkannagari and Serena Massari and Yashwanth Ashok and Ezeogo Obaji and Yves Nkizinkinko and Bernhard L{\"u}scher and Oriana Tabarrini and Lari Lehti{\"o}",
year = "2018",
month = "8",
day = "5",
doi = "10.1016/j.ejmech.2018.06.047",
language = "English (US)",
volume = "156",
pages = "93--102",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - 4-(Phenoxy) and 4-(benzyloxy)benzamides as potent and selective inhibitors of mono-ADP-ribosyltransferase PARP10/ARTD10

AU - Murthy, Sudarshan

AU - Desantis, Jenny

AU - Verheugd, Patricia

AU - Maksimainen, Mirko M.

AU - Venkannagari, Harikanth

AU - Massari, Serena

AU - Ashok, Yashwanth

AU - Obaji, Ezeogo

AU - Nkizinkinko, Yves

AU - Lüscher, Bernhard

AU - Tabarrini, Oriana

AU - Lehtiö, Lari

PY - 2018/8/5

Y1 - 2018/8/5

N2 - 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.

AB - 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.

KW - ADP-Ribosylation

KW - ARTD

KW - Inhibitor

KW - PARP

KW - Structure-activity relationship

UR - http://www.scopus.com/inward/record.url?scp=85049333074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049333074&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2018.06.047

DO - 10.1016/j.ejmech.2018.06.047

M3 - Article

VL - 156

SP - 93

EP - 102

JO - European Journal of Medicinal Chemistry

T2 - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -