Fragment-Hopping-Based Discovery of a Novel Chemical Series of Proto-Oncogene PIM-1 Kinase Inhibitors 英文参考文献.docVIP

Fragment-Hopping-BasedDiscoveryofaNovelChemical SeriesofProto-OncogenePIM-1KinaseInhibitors GustavoSaluste,MariaI.Albarran,RosaM.Alvarez,ObduliaRabal¤a,MiguelAngelOrtega, CarmenBlanco,GuidoKurz¤b,AntonioSalgado,PaoloPevarello¤c,JamesR.Bischoff¤d,JoaquinPastor, JulenOyarzabal*¤a ExperimentalTherapeuticsProgram,SpanishNationalCancerResearchCentre(CNIO),C/MelchorFerna′ndez Almagro3,Madrid,Spain Abstract A new chemical series, triazolo[4,5-b]pyridines, has been identified as an inhibitor of PIM-1 by a chemotype hopping strategy based on a chemically feasible fragment database. In this case, structure-based virtual screening and in silico chemogenomicsprovideaddedvaluetothepreviouslyreportedstrategyofprioritizingamongproposednovelscaffolds. Pairwisecomparisonbetweencompound3,recentlydiscontinuedfromPhaseIclinicaltrials,andmolecule8,bearingthe selectednovelscaffold,showsthattheprimaryactivitiesaresimilar(IC50inthe20to150nMrange).Atthesametime,some ADMEproperties(forexample,anincreaseofmorethan45%inmetabolicstabilityinhumanlivermicrosomes)andtheoff- target selectivity (for example, an increase of more than 2log units in IC50 vs. FLT3) are improved, and the intellectual property (IP) position is enhanced. The discovery of a reliable starting point that fulfills critical criteria for a plausible medicinalchemistryprojectisdemonstratedinthisprospectivestudy. Citation:SalusteG,AlbarranMI,AlvarezRM,RabalO,OrtegaMA,etal.(2012)Fragment-Hopping-BasedDiscoveryofaNovelChemicalSeriesofProto-Oncogene PIM-1KinaseInhibitors.PLoSONE7(10):e45964.doi:10.1371/journal.pone.0045964 Editor:Ramo′nCampos-Olivas,SpanishNationalCancerCenter,Spain ReceivedJune7,2012;AcceptedAugust23,2012;PublishedOctober24,2012 Copyright: ? 2012 Saluste et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited. Funding: The authors gratefully