Результаты исследований: Научные публикации в периодических изданиях › статья
Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy. / Papeo, G.; Posteri, H.; Borghi, D.; Busel, A.A.; Caprera, F.; Casale, E.; Ciomei, M.; Cirla, A.; Corti, E.; D'Anello, M.; Fasolini, M.; Forte, B.; Galvani, A.; Isacchi, A.; Khvat, A.; Krasavin, M.Y.; Lupi, R.; Orsini, P.; Perego, R.; Pesenti, E.; Pezzetta, D.; Rainoldi, S.; Riccardi-Sirtori, F.; Scolaro, A.; Sola, F.; Zuccotto, F.; Felder, E.R.; Donati, D.; Montagnoli, A.
в: Journal of Medicinal Chemistry, № 17, 2015, стр. 6875-6898.Результаты исследований: Научные публикации в периодических изданиях › статья
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TY - JOUR
T1 - Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy
AU - Papeo, G.
AU - Posteri, H.
AU - Borghi, D.
AU - Busel, A.A.
AU - Caprera, F.
AU - Casale, E.
AU - Ciomei, M.
AU - Cirla, A.
AU - Corti, E.
AU - D'Anello, M.
AU - Fasolini, M.
AU - Forte, B.
AU - Galvani, A.
AU - Isacchi, A.
AU - Khvat, A.
AU - Krasavin, M.Y.
AU - Lupi, R.
AU - Orsini, P.
AU - Perego, R.
AU - Pesenti, E.
AU - Pezzetta, D.
AU - Rainoldi, S.
AU - Riccardi-Sirtori, F.
AU - Scolaro, A.
AU - Sola, F.
AU - Zuccotto, F.
AU - Felder, E.R.
AU - Donati, D.
AU - Montagnoli, A.
PY - 2015
Y1 - 2015
N2 - © 2015 American Chemical Society.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, respectivel
AB - © 2015 American Chemical Society.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, respectivel
U2 - 10.1021/acs.jmedchem.5b00680
DO - 10.1021/acs.jmedchem.5b00680
M3 - Article
SP - 6875
EP - 6898
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 17
ER -
ID: 4005084