2. Academic Validation
  3. Cerpegin-derived furo[3,4-c]pyridine-3,4(1H,5H)-diones enhance cellular response to interferons by de novo pyrimidine biosynthesis inhibition

Cerpegin-derived furo[3,4-c]pyridine-3,4(1H,5H)-diones enhance cellular response to interferons by de novo pyrimidine biosynthesis inhibition

  • Eur J Med Chem. 2020 Jan 15;186:111855. doi: 10.1016/j.ejmech.2019.111855.
Simon Hayek 1,  Nicolas Pietrancosta 1,  Anna A Hovhannisyan 2,  Rodolphe Alves de Sousa 1,  Nassima Bekaddour 1,  Laura Ermellino 3,  Enzo Tramontano 4,  Stéphanie Arnould 5,  Claude Sardet 5,  Julien Dairou 6,  Olivier Diaz 7,  Vincent Lotteau 7,  Sébastien Nisole 8,  Gagik Melikyan 9,  Jean-Philippe Herbeuval 1,  Pierre-Olivier Vidalain 10
Affiliations

Affiliations

  • 1 Chimie et Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, CNRS UMR8601, Paris, France.
  • 2 Department of Organic Chemistry, Yerevan State University, Yerevan, Armenia.
  • 3 Chimie et Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, CNRS UMR8601, Paris, France; Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
  • 4 Laboratory of Molecular Virology, Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
  • 5 Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier, Montpellier, France.
  • 6 Chimie Bio-inorganique des Dérivés Soufrés et Pharmacochimie (CBDSP), Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, CNRS UMR8601, Paris, France.
  • 7 Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, Université Lyon 1, ENS de Lyon, Lyon, France.
  • 8 Institut de Recherche en Infectiologie de Montpellier, CNRS UMR9004, Université de Montpellier, Montpellier, France.
  • 9 Department of Organic Chemistry, Yerevan State University, Yerevan, Armenia. Electronic address: [email protected].
  • 10 Chimie et Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, CNRS UMR8601, Paris, France. Electronic address: [email protected].
PMID: 31740051 DOI: 10.1016/j.ejmech.2019.111855
Abstract

There is an increasing interest in the field of Cancer therapy for small compounds targeting pyrimidine biosynthesis, and in particular Dihydroorotate Dehydrogenase (DHODH), the fourth Enzyme of this metabolic pathway. Three available DHODH structures, featuring three different known inhibitors, were used as templates to screen in silico an original chemical library from Erevan University. This process led to the identification of P1788, a compound chemically related to the alkaloid cerpegin, as a new class of pyrimidine biosynthesis inhibitors. In line with previous reports, we investigated the effect of P1788 on the cellular innate immune response. Here we show that pyrimidine depletion by P1788 amplifies cellular response to both type-I and type II interferons, but also induces DNA damage as assessed by γH2AX staining. Moreover, the addition of inhibitors of the DNA damage response led to the suppression of the P1788 stimulatory effects on the interferon pathway. This demonstrates that components of the DNA damage response are bridging the inhibition of pyrimidine biosynthesis by P1788 to the interferon signaling pathway. Altogether, these results provide new insights on the mode of action of novel pyrimidine biosynthesis inhibitors and their development for Cancer therapies.

Keywords

Cerpegin; DHODH; DNA damage response; Interferon; Pyrimidine biosynthesis.

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