RESUMEN
We describe a novel series of potent inhibitors of the kinase activity of mTOR. The compounds display good selectivity relative to other PI3K-related kinase family members and, in cellular assays, inhibit both mTORC1 and mTORC2 complexes and exhibit good antiproliferative activity.
Asunto(s)
Antineoplásicos/química , Diaminas/química , Morfolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Pirimidinas/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular , Diaminas/síntesis química , Diaminas/farmacología , Descubrimiento de Drogas , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Morfolinas/síntesis química , Morfolinas/farmacología , Complejos Multiproteicos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Proteínas , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
We have previously described poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors based on a substituted benzyl-phthalazinone scaffold. As an alternative chemical template, a novel series of alkoxybenzamides were developed with restricted conformation through intramolecular hydrogen bond formation; the compounds exhibit low nM enzyme and cellular activity as PARP-1 inhibitors.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Química Farmacéutica , Diseño de Fármacos , Inhibidores Enzimáticos/química , Células HeLa , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Estructura Molecular , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Poly(ADP-ribose) polymerase activation is an immediate cellular response to metabolic-, chemical-, or ionizing radiation-induced DNA damage and represents a new target for cancer therapy. In this article, we disclose a novel series of substituted 4-benzyl-2 H-phthalazin-1-ones that possess high inhibitory enzyme and cellular potency for both PARP-1 and PARP-2. Optimized compounds from the series also demonstrate good pharmacokinetic profiles, oral bioavailability, and activity in vivo in an SW620 colorectal cancer xenograft model. 4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2 H-phthalazin-1-one (KU-0059436, AZD2281) 47 is a single digit nanomolar inhibitor of both PARP-1 and PARP-2 that shows standalone activity against BRCA1-deficient breast cancer cell lines. Compound 47 is currently undergoing clinical development for the treatment of BRCA1- and BRCA2-defective cancers.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Ftalazinas/síntesis química , Ftalazinas/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Perros , Inhibidores Enzimáticos/química , Humanos , Ratones , Estructura Molecular , Ftalazinas/química , Piperazinas/química , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
We have previously described the discovery of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors based on a phthalazinone scaffold. Subsequent optimisation of inhibitory activity, metabolic stability and pharmacokinetic parameters has led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-one PARP-1 inhibitors which retain low nM cellular activity and show good stability in vivo and efficacy in cell based models.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Ftalazinas/síntesis química , Ftalazinas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Modelos Moleculares , Estructura Molecular , Ftalazinas/química , Poli(ADP-Ribosa) Polimerasa-1 , Ratas , Relación Estructura-ActividadRESUMEN
Screening of the Maybridge compound collection identified 4-arylphthalazinones as micromolar inhibitors of PARP-1 catalytic activity. Subsequent optimisation of both inhibitory activity and metabolic stability led to a novel series of meta-substituted 4-benzyl-2H-phthalazin-1-ones with low nanomolar, cellular activity as PARP-1 inhibitors and promising metabolic stability in vitro.