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Papeo, Gianluca; Posteri, Helena; Borghi, Daniela; Busel, Alina A.; Caprera, Francesco; Casale, Elena; Ciomei, Marina; Cirla, Alessandra; Corti, Emiliana; D’Anello, Matteo; Fasolini, Marina; Forte, Barbara; Galvani, Arturo; Isacchi, Antonella; Khvat, Alexander; Krasavin, Mikhail Y.; Lupi, Rosita; Orsini, Paolo; Perego, Rita; Pesenti, Enrico; Pezzetta, Daniele; Rainoldi, Sonia; Riccardi-Sirtori, Federico; Scolaro, Alessandra; Sola, Francesco; Zuccotto, Fabio; Felder, Eduard R.; Donati, Daniele; Montagnoli, Alessia
Journal of medicinal chemistry, 09/2015, Letnik: 58, Številka: 17Journal Article
The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-1-(4,4-difluorocyclohexyl)piperidin-4-yl-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
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Leto | Faktor vpliva | Izdaja | Kategorija | Razvrstitev | ||||
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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