RESUMEN
Histone acetyl transferases are important regulators of cellular homeostasis. This study describes a sensitive acetyl transferase electrophoretic mobility shift assay applicable both for kinetic analysis of acetyl transferase inhibitors and for high-throughput testing. Application of the assay for human GCN5L2 enabled dissection of inhibitor competition with respect to acetyl coenzyme A. Furthermore, we demonstrated that the assay can detect time-dependent inhibition of human GCN5L2 by reactive inhibitors.
Asunto(s)
Ensayo de Cambio de Movilidad Electroforética/métodos , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/metabolismo , Acetilcoenzima A/metabolismo , Animales , Línea Celular , Humanos , CinéticaRESUMEN
Hit to Lead optimization and SAR development led to the identification of the potent and selective benzo[d]imidazole inhibitor (17b) of Co-activator Associated Arginine Methyltransferase (CARM1).
Asunto(s)
Antineoplásicos/química , Bencimidazoles/química , Inhibidores Enzimáticos/química , Piperidinas/química , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Proteína-Arginina N-Metiltransferasas/metabolismo , Relación Estructura-ActividadRESUMEN
Design, synthesis, and SAR development led to the identification of the potent, novel, and selective pyrazole based inhibitor (7f) of Coactivator Associated Arginine Methyltransferase (CARM1).
Asunto(s)
Inhibidores Enzimáticos/química , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Pirazoles/química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Proteína-Arginina N-Metiltransferasas/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
This study reports the identification and Hits to Leads optimization of inhibitors of coactivator associated arginine methyltransferase (CARM1). Compound 7b is a potent, selective inhibitor of CARM1.
Asunto(s)
Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Técnicas Químicas Combinatorias , Estructura Molecular , Pirazoles/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Pirimidinas/síntesis química , Tiazoles/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Dasatinib , Femenino , Humanos , Técnicas In Vitro , Inflamación/sangre , Inflamación/inducido químicamente , Interleucina-2/antagonistas & inhibidores , Lipopolisacáridos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Moleculares , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Pirimidinas/farmacología , Tiazoles/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Animales , Dasatinib , Humanos , Células K562 , Ratones , Proteínas Proto-Oncogénicas c-abl/química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Tiazoles/farmacocinética , Familia-src Quinasas/químicaRESUMEN
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.
Asunto(s)
Amidas/farmacología , Antiinflamatorios/farmacología , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Artritis Experimental/terapia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Masculino , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.
Asunto(s)
Antiinflamatorios/química , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Relación Estructura-Actividad Cuantitativa , Quinoxalinas/química , Quinoxalinas/farmacocinética , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Disponibilidad Biológica , Citocinas/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Enlace de Hidrógeno , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Pirazinas/química , Pirazinas/farmacología , Quinoxalinas/farmacología , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , Secuencia de Aminoácidos , Sitios de Unión , Diseño de Fármacos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) was prepared to elucidate their structure-activity relationships (SAR), selectivity and cell activity in the T-cell proliferation assay. BMS-350751 (2) and BMS-358233 (3) are identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.
Asunto(s)
Anilidas/síntesis química , Anilidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , División Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Conformación Proteica , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/enzimologíaRESUMEN
A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in the T-cell proliferation assay. BMS-243117 (compound 2) is identified as a potent, and selective Lck inhibitor with good cellular activity (IC(50)=1.1 microM) against T-cell proliferation.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , Adenosina Trifosfato/metabolismo , Sitios de Unión/efectos de los fármacos , División Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad , Especificidad por Sustrato , Linfocitos T/efectos de los fármacos , Urea/químicaRESUMEN
A series of anilino(imidazoquinoxaline) analogues bearing solubilizing side chains at the 6- and 7-positions of the fused phenyl ring has been prepared and evaluated for inhibition against Lck enzyme and of T-cell proliferation. Significant improvement of the cellular activity was achieved over the initial lead, compound 2.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , División Celular/efectos de los fármacos , Humanos , Indicadores y Reactivos , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacosRESUMEN
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.