5a00

Structure of human PARP1 catalytic domain bound to an isoindolinone inhibitor

spinqualitylabelsall models 5a00, resolution 2.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5a00 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: D7N, SO4 Related: 4zzx, 4zzy, 4zzz Activity: NAD(+) ADP-ribosyltransferase, with EC number 2.4.2.30 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [PARP1_HUMAN] Involved in the base excision repair (BER) pathway, by catalyzing the poly(ADP-ribosyl)ation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism. This modification follows DNA damages and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks. Mediates the poly(ADP-ribosyl)ation of APLF and CHFR. Positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150. With EEF1A1 and TXK, forms a complex that acts as a T-helper 1 (Th1) cell-specific transcription factor and binds the promoter of IFN-gamma to directly regulate its transcription, and is thus involved importantly in Th1 cytokine production. Publication Abstract from PubMed 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. However all current compounds 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 around the unselective isoindolinone-4-carboxamide hits 10a and 10b, allowed us to subsequently discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoind ole-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. High resolution X-ray diffraction co-crystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity. Discovery of 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoind ole-4-carboxamide (NMS-P118): a Potent, Orally Available and Highly Selective PARP-1 Inhibitor for Cancer Therapy.,Papeo GM, Posteri H, Borghi D, Busel AA, Caprera F, Casale E, Ciomei M, Cirla A, Corti E, D'Anello M, Fasolini M, Forte B, Galvani A, Isacchi A, Khvat A, Krasavin MY, Lupi R, Orsini P, Perego R, Pesenti E, Pezzetta D, Rainoldi S, Riccardi-Sirtori F, Scolaro A, Sola F, Zuccotto F, Felder ER, Donati D, Montagnoli A J Med Chem. 2015 Jul 29. PMID:26222319 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Poly (ADP-ribose) polymerase

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