RESUMEN
The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.
Asunto(s)
Aminopiridinas/farmacología , Quinasa 8 Dependiente de Ciclina/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas/farmacología , Administración Oral , Aminopiridinas/administración & dosificación , Aminopiridinas/química , Animales , Disponibilidad Biológica , Células CACO-2 , Quinasa 8 Dependiente de Ciclina/metabolismo , Quinasas Ciclina-Dependientes/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Ratas , Ratas Wistar , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Bibliotecas de Moléculas Pequeñas/química , Solubilidad , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In a high-throughput screening campaign for c-Met kinase inhibitors, a thiadiazinone derivative with a carbamate group was identified as a potent in vitro inhibitor. Subsequent optimization guided by c-Met-inhibitor X-ray structures furnished new compound classes with excellent in vitro and in vivo profiles. The thiadiazinone ring of the HTS hit was first replaced by a pyridazinone followed by an exchange of the carbamate hinge binder with a 1,5-disubstituted pyrimidine. Finally an optimized compound, 22 (MSC2156119), with excellent in vitro potency, high kinase selectivity, long half-life after oral administration and in vivo anti-tumor efficacy at low doses, was selected as a candidate for clinical development.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridazinas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/metabolismo , Piridazinas/síntesis química , Piridazinas/química , Relación Estructura-ActividadRESUMEN
WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Evaluación Preclínica de Medicamentos/métodos , Luciferasas/antagonistas & inhibidores , Piridinas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Compuestos de Espiro/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Bioensayo/métodos , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Luciferasas/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Piridinas/administración & dosificación , Piridinas/química , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Bibliotecas de Moléculas Pequeñas/química , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: The mesenchymal-epithelial transition factor (c-Met) receptor, also known as hepatocyte growth factor receptor (HGFR), controls morphogenesis, a process that is physiologically required for embryonic development and tissue repair. Aberrant c-Met activation is associated with a variety of human malignancies including cancers of the lung, kidney, stomach, liver, and brain. In this study, we investigated the properties of two novel compounds developed to selectively inhibit the c-Met receptor in antitumor therapeutic interventions. EXPERIMENTAL DESIGN: The pharmacologic properties, c-Met inhibitory activity, and antitumor effects of EMD 1214063 and EMD 1204831 were investigated in vitro and in vivo, using human cancer cell lines and mouse xenograft models. RESULTS: EMD 1214063 and EMD 1204831 selectively suppressed the c-Met receptor tyrosine kinase activity. Their inhibitory activity was potent [inhibitory 50% concentration (IC50), 3 nmol/L and 9 nmol/L, respectively] and highly selective, when compared with their effect on a panel of 242 human kinases. Both EMD 1214063 and EMD 1204831 inhibited c-Met phosphorylation and downstream signaling in a dose-dependent fashion, but differed in the duration of their inhibitory activity. In murine xenograft models, both compounds induced regression of human tumors, regardless of whether c-Met activation was HGF dependent or independent. Both drugs were well tolerated and induced no substantial weight loss after more than 3 weeks of treatment. CONCLUSIONS: Our results indicate selective c-Met inhibition by EMD 1214063 and EMD 1204831 and strongly support clinical testing of these compounds in the context of molecularly targeted anticancer strategies.
Asunto(s)
Antineoplásicos/farmacología , Morfolinas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridazinas/farmacología , Pirimidinas/farmacología , Animales , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/administración & dosificación , Pirimidinas/administración & dosificación , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
RAF kinase plays a critical role in the RAF-MEK-ERK signaling pathway and inhibitors of RAF could be of use for the treatment of various cancer types. We have designed potent RAF-1 inhibitors bearing novel bicyclic heterocycles as key structural elements for the interaction with the hinge region. In both series exploration of the SAR was focussed on the substitution of the phenyl ring, which binds to the induced fit pocket. Overall, it was confirmed that incorporation of lipophilic substituents was needed for potent Raf inhibition and a number of potent analogues were obtained.
Asunto(s)
Bencimidazoles/química , Isoquinolinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Quinasas raf/antagonistas & inhibidores , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Sitios de Unión , Dominio Catalítico , Simulación por Computador , Diseño de Fármacos , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal , Relación Estructura-Actividad , Quinasas raf/metabolismoRESUMEN
The hydrazide group is a new oxidatively cleavable traceless linker for solid-phase chemistry. It can be readily introduced by hydrazide formation between a carboxy-functionalized resin and different substituted hydrazines. In order to achieve high yields in this step, new carboxylic acid resins were developed that are not prone to undesired imide formation upon activation of the carboxylic acid. The polymer-bound acyl hydrazides were successfully employed in various transformations, namely Heck, Suzuki, Sonogashira, and Stille couplings, as well as Wittig and Grignard reactions. Traceless release of the coupling products from the solid support is achieved selectively under mild conditions and in high purity by oxidation of the aryl hydrazides to acyl diazenes with Cu(II) salts or N-bromosuccinimide (NBS) and subsequent nucleophilic attack of the acyl diazene intermediates. Traceless cleavage by oxidation with NBS can be carried out as a two-step process in which stable acyl diazenes are first generated by treatment with NBS in the absence of a nucleophile. After removal of the reagents by simple resin washing, the traceless release is effected by the addition of methanol, which leads to products of high purity without any additional separation steps.
RESUMEN
The hydrazide group is an oxidatively cleavable traceless linker for solid-phase chemistry. This linker technology was used to develop a multistep solid-phase synthesis of an antibiotic that is active against Mycobacterium tuberculosis. Furthermore, we describe an efficient method for the traceless synthesis of 2-aminothiazoles that display dual inhibitory activity against the receptor tyrosine kinases VEGFR-2 and Tie-2. The synthesis method proceeds through 9 steps on the solid phase and should give access to a much larger library of 2-aminothiazoles, from which a new class of anti-angiogenesis drugs may be developed.
Asunto(s)
Antibacterianos/síntesis química , Técnicas Químicas Combinatorias/métodos , Inhibidores Enzimáticos/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidoresAsunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Tiazoles/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Técnicas Químicas Combinatorias/métodos , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Estructura Molecular , Receptor TIE-2 , Especificidad por Sustrato , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
New methods for the synthesis of acid-functionalized polystyrene and TentaGel resins are described; these methods serve to overcome problems with currently available resins and will be instrumental in spurring the use of carboxylic acid resins in solid phase chemistry.
Asunto(s)
Técnicas Químicas Combinatorias , Resinas Sintéticas/síntesis química , Ácidos Carboxílicos/química , Reactivos de Enlaces Cruzados , Éteres/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Four depsipeptide analogues of the insect neuropeptide proctolin (H-Arg-Tyr-Leu-Pro-Thr-OH) have been prepared, containing a single ester linkage between Arg(1) and Tyr(2), Tyr(2) and Leu(3), and between Pro(4) and Thr(5), respectively. A didepsipentapeptide containing an ester linkage between Tyr(2) and Leu(3) and between Pro(4) and Thr(5), has also been prepared. The depsipeptide 4 is the first example of a backbone-modified proctolin analogue which shows full myotropic activity.