RESUMEN
Inhibition of TGFß signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFß receptor (TGFßR) inhibitors in cancer therapy. To restrict the activity of TGFßR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFßR1 inhibitor 1 were prepared by appending 1 to a serine protease substrate and a half-life extension fatty acid carbon chain. The prodrugs were shown to be selectively metabolized in tumor tissues relative to the heart and blood and demonstrated a prolonged favorable increase in the tumor-to-heart ratio of the active drug in tissue distribution studies. Once-weekly administration of the most tissue-selective compound 10 provided anti-tumor efficacy comparable to the parent compound and reduced systemic exposure of the active drug.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Profármacos/uso terapéutico , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/metabolismo , Área Bajo la Curva , Estabilidad de Medicamentos , Femenino , Semivida , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Estructura Molecular , Miocardio/metabolismo , Neoplasias/metabolismo , Profármacos/química , Profármacos/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.
RESUMEN
JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.
RESUMEN
Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.
RESUMEN
The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.
Asunto(s)
Amidas/química , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Amidas/metabolismo , Amidas/farmacología , Sitios de Unión , Carbazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Janus Quinasa 3/antagonistas & inhibidores , Janus Quinasa 3/metabolismo , Simulación de Dinámica Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
The IAPs are key regulators of the apoptotic pathways and are commonly overexpressed in many cancer cells. IAPs contain one to three BIR domains that are crucial for their inhibitory function. The pro-survival properties of XIAP come from binding of the BIR domains to the pro-apoptotic caspases. The BIR3 domain of XIAP binds and inhibits caspase 9, while the BIR2 domain binds and inhibits the terminal caspases 3 and 7. While XIAP BIR3 inhibitors have previously been reported, they also inhibit cIAP1/2 and promote the release of TNFα, potentially limiting their therapeutic utility. This paper will focus on the optimization of selective XIAP BIR2 inhibitors leading to the discovery of highly potent benzodiazepinone 36 (IC50 = 45 nM), which has high levels of selectivity over XIAP BIR3 and cIAP1 BIR2/3 and shows efficacy in a xenograft pharmacodynamic model monitoring caspase activity while not promoting the release of TNFα in vitro.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Alanina/análogos & derivados , Alanina/síntesis química , Alanina/farmacocinética , Alanina/farmacología , Animales , Apoptosis/efectos de los fármacos , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacocinética , Benzodiazepinonas/farmacología , Western Blotting , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Femenino , Compuestos Heterocíclicos/farmacocinética , Humanos , Proteínas Inhibidoras de la Apoptosis/química , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Ratones Desnudos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Estructura Terciaria de Proteína , Ubiquitina-Proteína Ligasas , Proteína Inhibidora de la Apoptosis Ligada a X/química , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
XIAP is a key regulator of apoptosis, and its overexpression in cancer cells may contribute to their survival. The antiapoptotic function of XIAP derives from its BIR domains, which bind to and inhibit pro-apoptotic caspases. Most known IAP inhibitors are selective for the BIR3 domain and bind to cIAP1 and cIAP2 as well as XIAP. Pathways activated upon cIAP binding contribute to the function of these compounds. Inhibitors selective for XIAP should exert pro-apoptotic effects through competition with the terminal caspases. This paper details our synthetic explorations of a novel XIAP BIR2-selective benzazepinone screening hit with a focus on increasing BIR2 potency and overcoming high in vivo clearance. These efforts led to the discovery of benzoxazepinone 40, a potent BIR2-selective inhibitor with good in vivo pharmacokinetic properties which potentiates apoptotic signaling in a manner mechanistically distinct from that of known pan-IAP inhibitors.
Asunto(s)
Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Alanina/análogos & derivados , Alanina/síntesis química , Alanina/farmacocinética , Alanina/farmacología , Animales , Anticuerpos Monoclonales/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Femenino , Compuestos Heterocíclicos/farmacocinética , Humanos , Proteínas Inhibidoras de la Apoptosis/química , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Ratones Desnudos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Oxazepinas/síntesis química , Oxazepinas/farmacocinética , Oxazepinas/farmacología , Estructura Terciaria de Proteína , Ratas , Ubiquitina-Proteína Ligasas , Proteína Inhibidora de la Apoptosis Ligada a X/química , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of phenylacylsulfonamides has been prepared as antagonists of Bcl-2/Bcl-xL. In addition to potent binding affinities for both Bcl-2 and Bcl-xL, these compounds were shown to induce classical markers of apoptosis in isolated mitochondria. Overall weak cellular potency was improved by the incorporation of polar functionality resulting in compounds with moderate antiproliferative activity.
Asunto(s)
Antineoplásicos/síntesis química , Mitocondrias/efectos de los fármacos , Sulfonamidas/síntesis química , Proteína X Asociada a bcl-2/antagonistas & inhibidores , Proteína bcl-X/antagonistas & inhibidores , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , Citocromos c/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Mitocondrias/metabolismo , Modelos Moleculares , Sulfonamidas/farmacología , Proteína X Asociada a bcl-2/química , Proteína bcl-X/químicaRESUMEN
5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.
Asunto(s)
Antineoplásicos/síntesis química , Pirazoles/síntesis química , Pirimidinas/síntesis química , Sulfonamidas/síntesis química , Proteína X Asociada a bcl-2/antagonistas & inhibidores , Proteína bcl-X/antagonistas & inhibidores , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/química , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteína 11 Similar a Bcl2 , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Citocromos c/metabolismo , Humanos , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Modelos Moleculares , Unión Proteica , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/metabolismo , Pirazoles/farmacología , Pirimidinas/farmacología , Sulfonamidas/farmacología , Proteína X Asociada a bcl-2/química , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/química , Proteína bcl-X/metabolismoRESUMEN
Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.
Asunto(s)
Aminas/química , Aminopiridinas/síntesis química , Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Aminopiridinas/química , Aminopiridinas/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentration-time curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities.
Asunto(s)
Pirroles/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Alanina/análogos & derivados , Animales , Antígenos CD34/biosíntesis , Línea Celular Tumoral , Colágeno/química , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Humanos , Laminina/química , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Proteoglicanos/química , Transducción de Señal , Factores de TiempoRESUMEN
Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.
Asunto(s)
Aminopiridinas/síntesis química , Antineoplásicos/síntesis química , Dihidropiridinas/síntesis química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridonas/síntesis química , Administración Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Dihidropiridinas/farmacocinética , Dihidropiridinas/farmacología , Perros , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Solubilidad , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.
Asunto(s)
Antineoplásicos/síntesis química , Fosfotransferasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Piridonas/farmacología , Receptores de Factores de Crecimiento/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-met , Piridonas/síntesis química , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidoresRESUMEN
A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.
Asunto(s)
Aminopiridinas/síntesis química , Aminopiridinas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Pirroles/síntesis química , Pirroles/farmacología , Urea/síntesis química , Urea/farmacología , Aminopiridinas/química , Animales , Humanos , Ratones , Inhibidores de Proteínas Quinasas/química , Pirroles/química , Neoplasias Gástricas/inducido químicamente , Neoplasias Gástricas/patología , Relación Estructura-Actividad , Urea/análogos & derivados , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Diseño de Fármacos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirroles/farmacología , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Animales , Línea Celular , Inhibidores del Citocromo P-450 CYP3A , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Pirroles/síntesis química , Relación Estructura-Actividad , Triazinas/síntesis química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pirroles/química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptores de Factores de Crecimiento/antagonistas & inhibidores , Neoplasias Gástricas/tratamiento farmacológico , Triazinas/química , Animales , Células CACO-2/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas/efectos de los fármacos , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Glutatión Transferasa/antagonistas & inhibidores , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Conformación Proteica , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-met , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Factores de Crecimiento/metabolismo , Neoplasias Gástricas/sangre , Neoplasias Gástricas/enzimología , Relación Estructura-ActividadRESUMEN
A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.
Asunto(s)
Carcinoma/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Alanina/análogos & derivados , Animales , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos Fase II como Asunto , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Intestinos/efectos de los fármacos , Hígado/efectos de los fármacos , Ratones , Microsomas/efectos de los fármacos , Estructura Molecular , Profármacos/síntesis química , Profármacos/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirroles/síntesis química , Pirroles/química , Solubilidad , Estereoisomerismo , Triazinas/síntesis química , Triazinas/química , Agua/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Introduction of the 2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino group at the C-4 position of the pyrrolo[2,1-f][1,2,4] triazine scaffold led to the discovery of a novel sub-series of inhibitors of VEGFR-2 kinase activity. Subsequent SAR studies on the 1,3,5-oxadiazole ring appended to the C-6 position of this new sub-family of pyrrolotriazines resulted in the identification of low nanomolar inhibitors of VEGFR-2. Antitumor efficacy was observed with compound 37 against L2987 human lung carcinoma xenografts in athymic mice.
Asunto(s)
Ciclopropanos/química , Ciclopropanos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Triazinas/química , Triazinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Ciclopropanos/síntesis química , Inhibidores Enzimáticos del Citocromo P-450 , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Ratones Desnudos , Oxadiazoles/síntesis química , Oxadiazoles/química , Oxadiazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Pirroles/síntesis química , Pirroles/química , Pirroles/farmacología , Relación Estructura-Actividad , Triazinas/síntesis química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chronic myeloid leukemia (CML) is caused by the constitutively activated tyrosine kinase breakpoint cluster (BCR)-ABL. Current frontline therapy for CML is imatinib, an inhibitor of BCR-ABL. Although imatinib has a high rate of clinical success in early phase CML, treatment resistance is problematic, particularly in later stages of the disease, and is frequently mediated by mutations in BCR-ABL. Dasatinib (BMS-354825) is a multitargeted tyrosine kinase inhibitor that targets oncogenic pathways and is a more potent inhibitor than imatinib against wild-type BCR-ABL. It has also shown preclinical activity against all but one of the imatinib-resistant BCR-ABL mutants tested to date. Analysis of the crystal structure of dasatinib-bound ABL kinase suggests that the increased binding affinity of dasatinib over imatinib is at least partially due to its ability to recognize multiple states of BCR-ABL. The structure also provides an explanation for the activity of dasatinib against imatinib-resistant BCR-ABL mutants.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-abl/química , Pirimidinas/química , Tiazoles/química , Animales , Benzamidas , Cristalografía por Rayos X , Dasatinib , Resistencia a Antineoplásicos , Activación Enzimática , Humanos , Mesilato de Imatinib , Modelos Moleculares , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacología , Conformación Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-abl/metabolismo , Pirimidinas/metabolismo , Pirimidinas/farmacología , Relación Estructura-Actividad , Tiazoles/metabolismo , Tiazoles/farmacologíaRESUMEN
Substituted 3-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamides were identified as potent and selective inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2) kinase activity. The enzyme kinetics associated with the VEGFR-2 inhibition of 14 (Ki=49+/-9 nM) confirmed that the aminothiazole-based analogues are competitive with ATP. Analogue 14 demonstrated excellent kinase selectivity, favorable pharmacokinetic properties in multiple species, and robust in vivo efficacy in human lung and colon carcinoma xenograft models.