RESUMEN
The use of epigenetic bromodomain inhibitors as anticancer therapeutics has transitioned from targeting bromodomain extraterminal domain (BET) proteins into targeting non-BET bromodomains. The two most relevant non-BET bromodomain oncology targets are cyclic AMP response element-binding protein (CBP) and E1A binding protein P300 (EP300). To explore the growing CBP/EP300 interest, we developed a highly efficient two-step synthetic route for dimethylisoxazole-attached imidazo[1,2-a]pyridine scaffold-containing inhibitors. Our efficient two-step reactions enabled high-throughput synthesis of compounds designed by molecular modeling, which together with structure-activity relationship (SAR) studies facilitated an overarching understanding of selective targeting of CBP/EP300 over non-BET bromodomains. This led to the identification of a new potent and selective CBP/EP300 bromodomain inhibitor, UMB298 (compound 23, CBP IC50 72 nM and bromodomain 4, BRD4 IC50 5193 nM). The SAR we established is in good agreement with literature-reported CBP inhibitors, such as CBP30, and demonstrates the advantage of utilizing our two-step approach for inhibitor development of other bromodomains.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/antagonistas & inhibidores , Proteína p300 Asociada a E1A/antagonistas & inhibidores , Isoxazoles/química , Piridinas/química , Sitios de Unión , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteína p300 Asociada a E1A/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Piridinas/metabolismo , Piridinas/farmacología , Relación Estructura-Actividad , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
A reaction sequence involving three-component [3 + 2] cycloaddition of azomethine ylides followed by CuI-catalyzed cascade trifluoromethyl radical addition and cyclization is developed for diastereoselective synthesis of fused-tetrahydrobenzodiazepin-3-ones.
RESUMEN
The simultaneous inhibition of polo-like kinase 1 (PLK1) and BRD4 bromodomain by a single molecule could lead to the development of an effective therapeutic strategy for a variety of diseases in which PLK1 and BRD4 are implicated. Compound 23 has been found to be a potent dual kinase-bromodomain inhibitor (BRD4-BD1 IC50 = 28 nM, PLK1 IC50 = 40 nM). Compound 6 was found to be the most selective PLK1 inhibitor over BRD4 in our series (BRD4-BD1 IC50 = 2579 nM, PLK1 IC50 = 9.9 nM). Molecular docking studies with 23 and BRD4-BD1/PLK1 as well as with 6 corroborate the biochemical assay results.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Diseño de Fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas Nucleares/antagonistas & inhibidores , Conformación Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/patología , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Dominios Proteicos , Relación Estructura-Actividad , Células Tumorales Cultivadas , Quinasa Tipo Polo 1RESUMEN
The one-pot [3 + 2] cycloaddition of an azomethine ylide with a maleimide followed by another [3 + 2] cycloaddition of an azide with the second maleimide gives a 1,5-diamino intermediate which is used for a sequential aminomethylation reaction with formaldehyde through [5 + 1] annulation to afford a novel polycyclic scaffold bearing tetrahydroquinazoline, pyrrolidine, pyrrolidinedione, and N-substituted maleimide in stereoselective fashion.