RESUMEN
In mammalian cells, the aurora kinases (aurora-A, -B, and -C) play essential roles in regulating cell division. The expression of aurora-A and -B is elevated in a variety of human cancers and is associated with high proliferation rates and poor prognosis, making them attractive targets for anticancer therapy. AMG 900 is an orally bioavailable, potent, and highly selective pan-aurora kinase inhibitor that is active in taxane-resistant tumor cell lines. In tumor cells, AMG 900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG 900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG 900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG 900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG 900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG 900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG 900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.
Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Ftalazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Adulto , Animales , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , Benzamidas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Células HCT116 , Células HeLa , Histonas/metabolismo , Humanos , Ratones , Ratones Desnudos , Mutación , Neoplasias/enzimología , Neoplasias/patología , Organofosfatos/farmacología , Paclitaxel/farmacología , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Pirazoles/farmacología , Quinazolinas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB1 EC50 > 10 microM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.
Asunto(s)
Aminoquinolinas/síntesis química , Oxadiazoles/síntesis química , Receptor Cannabinoide CB2/agonistas , Administración Oral , Aminoquinolinas/administración & dosificación , Aminoquinolinas/farmacocinética , Animales , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Humanos , Modelos Moleculares , Oxadiazoles/administración & dosificación , Oxadiazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A novel class of potent and selective inhibitors of KDR incorporating an indazole moiety 1 is reported. The discovery, synthesis, and structure-activity relationships of this series of inhibitors have been investigated. The most promising compounds were also profiled to determine their pharmacokinetic properties and evaluated in a VEGF-induced vascular permeability assay.
Asunto(s)
Indazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Permeabilidad Capilar/efectos de los fármacos , Células Cultivadas , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Indazoles/síntesis química , Indazoles/química , Indazoles/metabolismo , Masculino , Ratones , Ratones Desnudos , Unión Proteica/fisiología , Inhibidores de Proteínas Quinasas/clasificación , Ratas , Ratas Sprague-Dawley , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.
Asunto(s)
Antineoplásicos/farmacología , Células Endoteliales/efectos de los fármacos , Naftalenos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neovascularización de la Córnea/sangre , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.
Asunto(s)
Antineoplásicos/farmacología , Células Endoteliales/efectos de los fármacos , Naftalenos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neovascularización de la Córnea/sangre , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5',4':5,6]pyrimido[1,2- a]benzimidazol-5(6 H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2- a]benzimidazol-5(6 H)-one ( 25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.