RESUMEN
Glycogen synthase kinase-3 plays an essential role in multiple biochemical pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacological intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homology with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compounds that are both potent and selective is challenging. A novel series of derivatives of 5-nitro-N2-(2-(pyridine-2ylamino)ethyl)pyridine-2,6-diamine were synthesized and have been shown to potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compounds activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The X-ray co-crystal structure of human GSK3-ß in complex with compound 2 is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Glucógeno Sintasa Quinasa 3/metabolismo , Semivida , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Concentración 50 Inhibidora , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Piridinas/metabolismo , Piridinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Cromatografía Liquida , Diseño de Fármacos , Humanos , Espectrometría de Masas , Fenoles/farmacología , Inhibidores de Proteínas Quinasas/química , Espectroscopía de Protones por Resonancia Magnética , Relación Estructura-ActividadRESUMEN
Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1R132H. This Letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of the compounds, leading to the identification of 19 as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, 19 efficiently inhibited the production of the biomarker 2-HG.
RESUMEN
A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAFV600E. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2.
Asunto(s)
Benzamidas/farmacología , Compuestos Heterocíclicos con 2 Anillos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Benzamidas/síntesis química , Benzamidas/química , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/química , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/metabolismo , Relación Estructura-ActividadRESUMEN
Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.
RESUMEN
In an effort to identify new antidiabetic agents, we have discovered a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine analogues which are inhibitors of human glycogen synthase kinase 3 (GSK3). We developed efficient synthetic routes to explore a wide variety of substitution patterns and convergently access a diverse array of analogues. Compound 1 (CHIR-911, CT-99021, or CHIR-73911) emerged from an exploration of heterocycles at the C-5 position, phenyl groups at C-4, and a variety of differently substituted linker and aminopyridine moieties attached at the C-2 position. These compounds exhibited GSK3 IC50s in the low nanomolar range and excellent selectivity. They activate glycogen synthase in insulin receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation of lead compounds 1 and 2 (CHIR-611 or CT-98014) in rodent models of type 2 diabetes revealed that single oral doses lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose transport, and improved glucose disposal without increasing insulin levels.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glucógeno Sintasa Quinasas/antagonistas & inhibidores , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Pirimidinas/farmacología , Animales , Células CHO , Cromatografía Líquida de Alta Presión , Cricetulus , Cristalografía por Rayos X , Inhibidores Enzimáticos/metabolismo , Humanos , Hipoglucemiantes/metabolismo , Espectrometría de Masas , Espectroscopía de Protones por Resonancia Magnética , Pirimidinas/química , Pirimidinas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The discovery of a highly potent and selective small molecule inhibitor 9 for in vitro target validation of MNK1/2 kinases is described. The aminopyrazine benzimidazole series was derived from an HTS hit and optimized by utilization of a docking model, conformation analysis, and binding pocket comparison against antitargets.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Sitios de Unión , Células CACO-2/efectos de los fármacos , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Simulación del Acoplamiento Molecular , Permeabilidad , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.
RESUMEN
While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, the full understanding of this kinase family has been restricted by the lack of highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor of the N-terminal kinase of RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted in highly optimized difluorophenol pyridine inhibitors of the RSK kinase family as demonstrated cellularly by the inhibition of YB1 phosphorylation. These compounds provide for the first time in vitro tools with an improved selectivity and potency profile to examine the importance of RSK signaling in cancer cells and to fully evaluate RSK as a therapeutic target.
Asunto(s)
Pirazoles/química , Piridinas/química , Pirimidinas/química , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Animales , Línea Celular , Cristalografía por Rayos X , Humanos , Masculino , Ratones , Modelos Moleculares , Fosforilación , Conformación Proteica , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas Sprague-Dawley , Transducción de Señal , Relación Estructura-Actividad , Proteína 1 de Unión a la Caja Y/metabolismoRESUMEN
[This corrects the article DOI: 10.1021/ml5002272.].
RESUMEN
Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate.
Asunto(s)
Antineoplásicos/síntesis química , Piridonas/síntesis química , Pirimidinas/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Ratones , Piridonas/farmacocinética , Piridonas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Relación Estructura-ActividadRESUMEN
Benzimidazole reverse amides were designed and synthesized as Pan RAF kinase inhibitors. Investigation of the structure-activity relationship of the compounds revealed that they were potent in vitro and exhibited desirable in vivo properties.
RESUMEN
UNLABELLED: The p90 ribosomal S6 kinase (RSK) family of serine/threonine kinases is expressed in a variety of cancers and its substrate phosphorylation has been implicated in direct regulation of cell survival, proliferation, and cell polarity. This study characterizes and presents the most selective and potent RSK inhibitors known to date, LJH685 and LJI308. Structural analysis confirms binding of LJH685 to the RSK2 N-terminal kinase ATP-binding site and reveals that the inhibitor adopts an unusual nonplanar conformation that explains its excellent selectivity for RSK family kinases. LJH685 and LJI308 efficiently inhibit RSK activity in vitro and in cells. Furthermore, cellular inhibition of RSK and its phosphorylation of YB1 on Ser102 correlate closely with inhibition of cell growth, but only in an anchorage-independent growth setting, and in a subset of examined cell lines. Thus, RSK inhibition reveals dynamic functional responses among the inhibitor-sensitive cell lines, underscoring the heterogeneous nature of RSK dependence in cancer. IMPLICATIONS: Two novel potent and selective RSK inhibitors will now allow a full assessment of the potential of RSK as a therapeutic target for oncology.
Asunto(s)
Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Secuencia de Aminoácidos , Procesos de Crecimiento Celular/efectos de los fármacos , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Modelos Moleculares , Datos de Secuencia Molecular , FosforilaciónRESUMEN
2-Amino-7-substituted benzoxazole analogs were identified by HTS as inhibitors of RSK2. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of improving in vitro and target modulation potency and physicochemical properties.
Asunto(s)
Benzoxazoles/química , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Benzoxazoles/síntesis química , Benzoxazoles/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Humanos , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Estructura Terciaria de Proteína , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Relación Estructura-ActividadRESUMEN
In recent years, the number of drug candidates with a covalent mechanism of action progressing through clinical trials or being approved by the FDA has increased significantly. And as interest in covalent inhibitors has increased, the technical challenges for characterizing and optimizing these inhibitors have become evident. A number of new tools have been developed to aid this process, but these have not gained wide-spread use. This review will highlight a number of methods and tools useful for prosecuting covalent inhibitor drug discovery programs.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Enzimas/metabolismo , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Compounds belonging to several scaffolds-quinazolines, quinolines and quinoxalines-were designed and synthesized as Raf kinase inhibitors. Scaffolds were assessed for in vitro Braf(V600E) inhibition, and overall kinase selectivity. Pharmacokinetic parameters for one of the scaffolds were also determined.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasas raf/antagonistas & inhibidores , Amidas/química , Sitios de Unión , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Modelos Moleculares , Estructura MolecularRESUMEN
Two scaffolds based on 5,6-fused heterocyclic backbones were designed and synthesized as Raf kinase inhibitors. The scaffolds were assessed for in vitro pan-Raf inhibition, activity in cell proliferation and target modulation assays, and pharmacokinetic parameters.
Asunto(s)
Amidas/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/síntesis química , Quinasas raf/antagonistas & inhibidores , Amidas/química , Amidas/farmacología , Sitios de Unión , Proliferación Celular , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A ligand-based 3D pharmacophore model for serine/threonine kinase CDC7 inhibition was created and successfully applied in the discovery of novel 2-(heteroaryl)-6,7-dihydrothieno[3,2-c]pyridin-4(5H)-ones. The pharmacophore model provided a hypothesis for lead generation missed by docking to a homology model. Medicinal chemistry exploration of the series revealed clear structure-activity relationships consistent with the pharmacophore model and pointed to further optimization opportunities.
RESUMEN
Analogs of the potent antifungal agent, bengazole A, were prepared and evaluated against Candida spp. in both microbroth dilution and disk diffusion assays.
Asunto(s)
Antifúngicos/química , Oxazoles/química , Antifúngicos/síntesis química , Antifúngicos/farmacología , Candida/efectos de los fármacos , Pruebas Antimicrobianas de Difusión por Disco , Oxazoles/síntesis química , Oxazoles/farmacología , Relación Estructura-ActividadRESUMEN
The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.