5A00

Structure of human PARP1 catalytic domain bound to an isoindolinone inhibitor

Summary for 5A00

• Entry DOI: 10.2210/pdb5a00/pdb
• Related: 4ZZX 4ZZY 4ZZZ
• Descriptor: POLY [ADP-RIBOSE] POLYMERASE 1, 2-[1-(4,4-Difluorocyclohexyl)-piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: transferase, human parp1, artd1
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 41007.78

Authors

Casale, E.,Fasolini, M.,Papeo, G.,Posteri, H.,Borghi, D.,Busel, A.A.,Caprera, F.,Ciomei, M.,Cirla, A.,Corti, E.,DAnello, M.,Fasolini, M.,Felder, E.R.,Forte, B.,Galvani, A.,Isacchi, A.,Khvat, A.,Krasavin, M.Y.,Lupi, R.,Orsini, P.,Perego, R.,Pesenti, E.,Pezzetta, D.,Rainoldi, S.,RiccardiSirtori, F.,Scolaro, A.,Sola, F.,Zuccotto, F.,Donati, D.,Montagnoli, A. (deposition date: 2015-04-15, release date: 2015-08-12, Last modification date: 2024-05-08)

Primary citation

Papeo, G.M.E.,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.
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.
J.Med.Chem., 58:6875-, 2015

PubMed Abstract: 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.

PubMed: 26222319
DOI: 10.1021/ACS.JMEDCHEM.5B00680

Experimental method

X-RAY DIFFRACTION (2.75 Å)