nms-p118 and Pancreatic-Neoplasms

nms-p118 has been researched along with Pancreatic-Neoplasms* in 1 studies

Other Studies

1 other study(ies) available for nms-p118 and Pancreatic-Neoplasms

ArticleYear
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.
    Journal of medicinal chemistry, 2015, Sep-10, Volume: 58, Issue:17

    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.

    Topics: Administration, Oral; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Cell Proliferation; Dacarbazine; Drug Screening Assays, Antitumor; Female; Heterografts; High-Throughput Screening Assays; Humans; Isoindoles; Mice, Inbred BALB C; Mice, Nude; Microsomes, Liver; Models, Molecular; Neoplasm Transplantation; Pancreatic Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Rats, Sprague-Dawley; Structure-Activity Relationship; Temozolomide; Triple Negative Breast Neoplasms

2015