RESUMEN
Src-null mice have higher bone mass because of decreased bone resorption and increased bone formation, whereas Abl-null mice are osteopenic, because of decreased bone formation. Compound I, a potent inhibitor of Src in an isolated enzyme assay (IC(50) 0.55 nM) and a Src-dependent cell growth assay, with lower activity on equivalent Abl-based assays, potently, but biphasically, accelerated differentiation of human mesenchymal stem cells to an osteoblast phenotype (1-10 nM). Compound I (≥0.1 nM) also activated osteoblasts and induced bone formation in isolated neonatal mouse calvariae. Compound I required higher concentrations (100 nM) to inhibit differentiation and activity of osteoclasts. Transcriptional profiling (TxP) of calvaria treated with 1 µM compound I revealed down-regulation of osteoclastic genes and up-regulation of matrix genes and genes associated with the osteoblast phenotype, confirming compound I's dual effects on bone resorption and formation. In addition, calvarial TxP implicated calcitonin-related polypeptide, ß (ß-CGRP) as a potential mediator of compound I's osteogenic effect. In vivo, compound I (1 mg/kg s.c.) increased vertebral trabecular bone volume 21% (microcomputed tomography) in intact female mice. Increased trabecular volume was also detected histologically in a separate bone, the femur, particularly in the secondary spongiosa (100% increase), which underwent a 171% increase in bone formation rate, a 73% increase in mineralizing surface, and a 59% increase in mineral apposition rate. Similar effects were observed in ovariectomized mice with established osteopenia. We conclude that the Src inhibitor compound I is osteogenic, presumably because of its potent stimulation of osteoblast differentiation and activation, possibly mediated by ß-CGRP.
Asunto(s)
Osteogénesis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Familia-src Quinasas/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Diferenciación Celular , Perfilación de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Osteoblastos/citología , Osteoblastos/efectos de los fármacos , Osteoclastos/citología , Osteoclastos/efectos de los fármacosRESUMEN
A series of substituted benzo[c][2,7]-naphthyridines were prepared and showed good potency in inhibiting PDK-1. The synthesis and SAR of this series of compounds are presented as well as the X-ray crystal structure of one of these analogs in a complex with PDK-1.
Asunto(s)
Antineoplásicos/química , Naftiridinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Sitios de Unión , Cristalografía por Rayos X , Humanos , Conformación Molecular , Naftiridinas/síntesis química , Naftiridinas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
Checkpoint deficiency of malignant cells can be exploited in cancer drug discovery. Compounds that selectively kill checkpoint-deficient cells versus checkpoint-proficient cells can be utilized to preferentially target tumor cells, while sparing normal cells. The protein p21(Wafl/Cipl/Sdi1) (hereafter referred to as p21) inhibits progression of the cell cycle by inhibiting the activity of G1 kinases (cyclin D/cdk4 and cyclin E-cdk2) and the G2 kinase (cyclin B/cdkl) in response to DNA damage or abnormal DNA content. The expression of p21 is often low in human cancer cells due to frequent loss of the upstream activator, p53, and is associated with poor prognosis in some cancer patients. Using an isogenic pair of cell lines, HCT116 (p21+/+) and 80S14 (p21-/-), we have disclosed previously a novel series of pyrazolo[1,5-a]pyrimidines that preferentially kill the p21-deficient cells. We will present the synthesis, biological activities and SAR study of a series of pyrazolo[1,5-a]pyrimidines with an optimized phenyl amide moiety at the C-7 position. The mechanism of action of these compounds will also be discussed.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Pirazoles/química , Pirimidinas/química , Amidas/química , Animales , Antineoplásicos/química , Línea Celular Tumoral , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Humanos , Ratones , Ratones Desnudos , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
It has been previously reported that appropriately substituted 4-anilinoquinoline-3-carbonitriles are potent inhibitors of Src kinase, with biological activity in vitro and in vivo. Structural modifications to these compounds have been explored, providing the 4-anilinobenzo[g]quinoline-3-carbonitriles as a series with enhanced Src inhibitory properties. The synthesis and structure-activity relationships of these 4-anilino-7,8-dialkoxybenzo[g]quinoline-3-carbonitriles are presented here. Analogues with cyclic basic amine groups attached via ethoxy linkages at the C-8 position were the most active in vitro, with subnanomolar IC50 values against Src kinase observed for a majority of the compounds synthesized. Compound 17d was more potent in vitro than the analogously substituted 4-anilinoquinoline-3-carbonitrile SKI-606, which is undergoing evaluation in clinical trials. The most potent analogue synthesized was 17a, with an IC50 of 0.15 nM against Src kinase and with an IC50 of 10 nM against Src-transformed fibroblasts. Molecular modeling studies provided a rationale for the exceptional activity observed for these compounds, with favorable van der Waals interactions playing the major role. Compound 17c was found to be highly selective for Src kinase when tested against a panel of other kinases, with modest selectivity versus the Src family kinases Lyn and Fyn. Following ip dosing at 50 mg/kg, analogues 17c and 17d were shown to have plasma levels that significantly exceeded the cellular IC50 values against Src-transformed fibroblasts. In an Src-transformed fibroblast xenograft model, both compounds exhibited a significant inhibition of tumor growth.
Asunto(s)
Compuestos de Anilina/síntesis química , Antineoplásicos/síntesis química , Nitrilos/síntesis química , Quinolinas/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transformación Celular Neoplásica , Fibroblastos/patología , Humanos , Ratones , Modelos Moleculares , Nitrilos/química , Nitrilos/farmacología , Fosforilación , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-Actividad , Tirosina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Familia-src Quinasas/metabolismoRESUMEN
We previously reported that several 7-alkoxy-4-phenylamino-3-quinolinecarbonitriles were potent inhibitors of Src kinase activity. We disclose here a new highly efficient and versatile route to these compounds, which are also potent inhibitors of Abl kinase.
Asunto(s)
Nitrilos/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Quinolinas/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Nitrilos/química , Nitrilos/farmacología , Quinolinas/química , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of antiproliferative agents containing pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides, selective for p21-deficient cells, were identified by high-throughput screening. Exploration of the SAR relationships in the headpiece, core, and tailpiece is described. Strict steric, positional, and electronic requirements were observed, with a clear preference for both core nitrogens, a thienoyl headpiece, and meta substituted tailpiece.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Proliferación Celular/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Simulación por Computador , Evaluación Preclínica de Medicamentos , Humanos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Proteína Oncogénica p21(ras)/antagonistas & inhibidores , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/antagonistas & inhibidoresRESUMEN
New 4-phenylamino-3-quinolinecarbonitriles with a 7-ethynyl group substituted by a pyridine, phenyl or thiophene ring containing basic water solubilizing groups were prepared and evaluated as Src kinase inhibitors. Of these new analogs, potent activity was observed with compounds having a (2,4-dichloro-5-methoxyphenyl)amino group at C-4, a methoxy or ethoxy group at C-6, and a pyridyl group bearing a dimethylamine or N-methylpiperazine on the ethynyl group at C-7.
Asunto(s)
Quinolinas/farmacología , Agua/química , Familia-src Quinasas/antagonistas & inhibidores , Quinolinas/química , SolubilidadRESUMEN
On the basis of a screening lead from an assay using a pair of p21 isogenic cell lines (p21-proficient cells and p21-deficient cells) to identify chemoselective agents, a series of novel thieno[2,3-d]pyrimidin-4(1H)-one-based analogs was prepared. Some analogs inhibited the growth of human colon tumor cells.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Pirimidinonas/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
A novel series of inhibitors of cancer cell proliferation, selective against p21 cell cycle checkpoint-disrupted cells vs. cells with intact p21 checkpoint, were identified by high-throughput screening. Optimization of both ends of the lead molecule to improve potency, using parallel synthesis and iterative design, is described. The 2-(1,4-dibenzodioxane)-substituted derivative 14 was identified as a highly selective and potent agent displaying an IC50 of 91 nM in the p21-deficient cell line.
Asunto(s)
Antineoplásicos/síntesis química , Pirimidinonas/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Pirimidinonas/farmacología , Relación Estructura-Actividad , Tubulina (Proteína)/efectos de los fármacosRESUMEN
Several 7-alkoxy-4-anilino-3-quinolinecarbonitriles were synthesized and evaluated for Src kinase inhibitory activity. Optimal inhibition of both Src enzymatic and cellular activity was seen with analogues having a 2,4-dichloro-5-methoxyaniline group at C-4. Compound 18, which has a 1-methylpiperidinemethoxy group at C-7, showed in vivo activity in a xenograft model.