| Added by | standudu |
|---|---|
| Group name | EquipeCTCS |
| Item Type | Journal Article |
| Title | Cerpegin-derived furo[3,4-c]pyridine-3,4(1H,5H)-diones enhance cellular response to interferons by de novo pyrimidine biosynthesis inhibition |
| Creator | Hayek et al. |
| Author | Simon Hayek |
| Author | Nicolas Pietrancosta |
| Author | Anna A. Hovhannisyan |
| Author | Rodolphe Alves de Sousa |
| Author | Nassima Bekaddour |
| Author | Laura Ermellino |
| Author | Enzo Tramontano |
| Author | Stéphanie Arnould |
| Author | Claude Sardet |
| Author | Julien Dairou |
| Author | Olivier Diaz |
| Author | Vincent Lotteau |
| Author | Sébastien Nisole |
| Author | Gagik Melikyan |
| Author | Jean-Philippe Herbeuval |
| Author | Pierre-Olivier Vidalain |
| 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 ?H2AX 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. |
| Publication | European Journal of Medicinal Chemistry |
| Volume | 186 |
| Pages | 111855 |
| Date | Jan 15, 2020 |
| Journal Abbr | Eur J Med Chem |
| Language | eng |
| DOI | 10.1016/j.ejmech.2019.111855 |
| ISSN | 1768-3254 |
| Library Catalog | PubMed |
| Extra | 00000 PMID: 31740051 |
| Tags | Cerpegin, DHODH, DNA damage response, Interferon, original, Pyrimidine biosynthesis |
| Date Added | 2020/01/21 - 10:47:46 |
| Date Modified | 2020/01/21 - 11:25:19 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
