RESUMEN
Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors.
Asunto(s)
Antineoplásicos/química , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/química , Ácidos Hidroxámicos/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Ratones , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Histone deacetylase (HDAC) inhibitors have shown promising clinical activity in the treatment of hematologic malignancies, but their activity in solid tumor indications has been limited. Most HDAC inhibitors in clinical development only transiently induce histone acetylation in tumor tissue. Here, we sought to identify a "second-generation" class I HDAC inhibitor with prolonged pharmacodynamic response in vivo, to assess whether this results in superior antitumoral efficacy. EXPERIMENTAL DESIGN: To identify novel HDAC inhibitors with superior pharmacodynamic properties, we developed a preclinical in vivo tumor model, in which tumor cells have been engineered to express fluorescent protein dependent on HDAC1 inhibition, thereby allowing noninvasive real-time evaluation of the tumor response to HDAC inhibitors. RESULTS: In vivo pharmacodynamic analysis of 140 potent pyrimidyl-hydroxamic acid analogues resulted in the identification of JNJ-26481585. Once daily oral administration of JNJ-26481585 induced continuous histone H3 acetylation. The prolonged pharmacodynamic response translated into complete tumor growth inhibition in Ras mutant HCT116 colon carcinoma xenografts, whereas 5-fluorouracil was less active. JNJ-26481585 also fully inhibited the growth of C170HM2 colorectal liver metastases, whereas again 5-fluorouracil/Leucovorin showed modest activity. Further characterization revealed that JNJ-26481585 is a pan-HDAC inhibitor with marked potency toward HDAC1 (IC(50), 0.16 nmol/L). CONCLUSIONS: The potent antitumor activity as a single agent in preclinical models combined with its favorable pharmacodynamic profile makes JNJ-26481585 a promising "second-generation" HDAC inhibitor. The compound is currently in clinical studies, to evaluate its potential applicability in a broad spectrum of both solid and hematologic malignancies.
Asunto(s)
Antineoplásicos/administración & dosificación , Inhibidores de Histona Desacetilasas/administración & dosificación , Ácidos Hidroxámicos/administración & dosificación , Neoplasias/tratamiento farmacológico , Animales , Apoptosis , Proliferación Celular , Neoplasias del Colon/patología , Fluorouracilo/farmacología , Histonas/química , Humanos , Concentración 50 Inhibidora , Neoplasias Hepáticas/secundario , Proteínas Luminiscentes/química , Masculino , Ratones , Metástasis de la Neoplasia , Trasplante de NeoplasiasRESUMEN
Based on the structure of R115777 (tipifarnib, Zarnestra), a series of farnesyltransferase inhibitors have been synthesized by modification of the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacement by 5-membered rings. This has yielded a novel series of potent farnesyltransferase inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Quinolonas/farmacología , Antineoplásicos/química , Inhibidores Enzimáticos/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Quinolonas/químicaRESUMEN
A series of pyrimidyl-5-hydroxamic acids was prepared for evaluation as inhibitors of histone deacetylase (HDAC). Amino-2-pyrimidinyl can be used as a linker to provide HDAC inhibitors of good enzymatic potency.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Femenino , Células HeLa , Humanos , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Estructura Molecular , Pirimidinas/química , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Compuestos Heterocíclicos/síntesis química , Quinolonas/síntesis química , Quinolonas/farmacología , Triazoles/síntesis química , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Cinética , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Conformación Molecular , Quinolonas/administración & dosificación , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , División Celular/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Farnesiltransferasa , Cinética , Conformación Molecular , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/farmacología , Relación Estructura-ActividadRESUMEN
The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.