5 research outputs found
Natural products as templates for bioactive compound libraries: Part 2. Novel modifications of vasicine (peganine) core via
Meteorite-catalyzed syntheses of nucleosides and of other prebiotic compounds from formamide under proton irradiation
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
The
nuclear protein polyÂ(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)Âpiperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1<i>H</i>-isoindole-4-carboxamide (NMS-P118, <b>20by</b>).
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 <b>20by</b> with both PARP-1 and PARP-2
catalytic domain proteins allowed rationalization of the observed
selectivity