Titolo:  Cerpegin-derived furo[3,4-c]pyridine-3,4(1H,5H)-diones enhance cellular response to interferons by de novo pyrimidine biosynthesis inhibition
Data di pubblicazione:  2020
Data di prima pubblicazione on-line:  2019
Autori:  Hayek, S.; Pietrancosta, N.; Hovhannisyan, A. A.; Alves de Sousa, R.; Bekaddour, N.; Ermellino, L.; Tramontano, E.; Arnould, S.; Sardet, C.; Dairou, J.; Diaz, O.; Lotteau, V.; Nisole, S.; Melikyan, G.; Herbeuval, J. -P.; Vidalain, P. -O.
Numero degli autori:  16
Lingua:  Inglese
Presenza coautori internazionali: 
Volume:  186
Pagina iniziale:  111855
Numero di pagine:  13
Digital Object Identifier (DOI):  http://dx.doi.org/10.1016/j.ejmech.2019.111855
Codice identificativo Pubmed:  31740051
Codice identificativo Scopus:  2-s2.0-85075360136
Codice identificativo ISI:  WOS:000509616800013
URL:  http://www.journals.elsevier.com/european-journal-of-medicinal-chemistry/
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.
Parole chiave:  Cerpegin; DHODH; DNA damage response; Interferon; Pyrimidine biosynthesis
Tipologia: 1.1 Articolo in rivista

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