RESUMEN
ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.
Asunto(s)
Aminopiridinas/farmacología , Antineoplásicos/farmacología , Compuestos de Fenilurea/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Familia-src Quinasas/antagonistas & inhibidores , Aminopiridinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Aurora Quinasa B , Aurora Quinasas , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Femenino , Histonas/antagonistas & inhibidores , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leucemia Experimental/tratamiento farmacológico , Leucemia Experimental/enzimología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Estructura Molecular , Células 3T3 NIH , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/uso terapéutico , Factores de Tiempo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PARP-1, the most abundant member of the PARP superfamily of nuclear enzymes, has emerged as a promising molecular target in the past decade particularly for the treatment of cancer. A number of PARP-1 inhibitors, including veliparab discovered at Abbott, have advanced into different stages of clinical trials. Herein we describe the development of a new tetrahydropyridopyridazinone series of PARP-1 inhibitors. Many compounds in this class, such as 20w, displayed excellent potency against the PARP-1 enzyme with a K(i) value of <1nM and an EC(50) value of 1nM in a C41 whole cell assay. The presence of the NH in the tetrahydropyridyl ring of the tetrahydropyridopyridazinone scaffold improved the pharmacokinetic properties over similar carbon based analogs. Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ).
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Piridazinas/farmacología , Piridinas/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , Femenino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/enzimología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Piridazinas/síntesis química , Piridazinas/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Four hinge-binding scaffolds have been explored for novel selective Aurora kinase inhibitors. The structure activity relationship, selectivity and pharmacokinetic profiles have been evaluated.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Aurora Quinasas , Línea Celular , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-ActividadRESUMEN
In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirazoles/química , Pirimidinas/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aminación , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Aurora Quinasa B , Aurora Quinasas , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Modelos Moleculares , Estructura Molecular , Pirimidinas/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In an effort to identify multi-targeted kinase inhibitors with a novel spectrum of kinase activity, a screen of Abbott proprietary KDR inhibitors against a broad panel of kinases was conducted and revealed a series of thienopyridine ureas with promising activity against the Aurora kinases. Modification of the diphenyl urea and C7 moiety of these compounds provided potent inhibitors with good pharmacokinetic profiles that were efficacious in mouse tumor models after oral dosing. Compound 2 (ABT-348) of this series is currently undergoing Phase I clinical trials in solid and hematological cancer populations.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Urea/farmacología , Animales , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Ratones , Inhibidores de Proteínas Quinasas/química , Factor A de Crecimiento Endotelial VascularRESUMEN
In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/farmacología , Animales , Aurora Quinasas , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Enlace de Hidrógeno , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.
Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA1/deficiencia , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Disponibilidad Biológica , Barrera Hematoencefálica/metabolismo , Carboplatino/administración & dosificación , Línea Celular Tumoral , Cristalografía por Rayos X , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Modelos Moleculares , Trasplante de Neoplasias , Estereoisomerismo , Relación Estructura-Actividad , Temozolomida , Trasplante HeterólogoRESUMEN
Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC(50) and cellular EC(50) values were as low as 1 nM or below. Compounds 24 (EC(50) = 3.7 nM) and 44 (EC(50) = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model.
Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Oxadiazoles/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Piridinas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos Alquilantes , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Sinergismo Farmacológico , Femenino , Humanos , Masculino , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Poli(ADP-Ribosa) Polimerasa-1 , Piridinas/farmacocinética , Piridinas/farmacología , Relación Estructura-Actividad , Temozolomida , Trasplante HeterólogoRESUMEN
Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been found to be overexpressed in a variety of hematopoietic malignancies and solid tumors. Benzothienopyrimidinones were discovered as a novel class of Pim inhibitors that potently inhibit all three Pim kinases with subnanomolar to low single-digit nanomolar K(i) values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones 3b (PDB code 3JYA), 6e (PDB code 3JYO), and 12b (PDB code 3JXW) were determined and used to guide SAR studies. Multiple compounds exhibited potent antiproliferative activity in K562 and MV4-11 cells with submicromolar EC(50) values. For example, compound 14j inhibited the growth of K562 cells with an EC(50) value of 1.7 muM and showed K(i) values of 2, 3, and 0.5 nM against Pim-1, Pim-2, and Pim-3, respectively. These novel Pim kinase inhibitors efficiently interrupted the phosphorylation of Bad in both K562 and LnCaP-Bad cell lines, indicating that their potent biological activities are mechanism-based. The pharmacokinetics of 14j was studied in CD-1 mice and shown to exhibit bioavailability of 76% after oral dosing. ADME profiling of 14j suggested a long half-life in both human and mouse liver microsomes, good permeability, modest protein binding, and no CYP inhibition below 20 muM concentration.
Asunto(s)
Antineoplásicos/síntesis química , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinonas/síntesis química , Tiofenos/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Permeabilidad de la Membrana Celular , Humanos , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Fosforilación , Conformación Proteica , Proteínas Proto-Oncogénicas c-pim-1/química , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirimidinonas/farmacocinética , Pirimidinonas/farmacología , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacología , Proteína Letal Asociada a bcl/metabolismoRESUMEN
Based on screening hit 1, a series of tricyclic quinoxalinones have been designed and evaluated for inhibition of PARP-1. Substitutions at the 7- and 8-positions of the quinoxalinone ring led to a number of compounds with good enzymatic and cellular potency. The tricyclic quinoxalinone class is sensitive to modifications of both the amine substituent and the tricyclic core. The synthesis and structure-activity relationship studies are presented.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Quinoxalinas/química , Quinoxalinas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis , Núcleo Celular/metabolismo , Reparación del ADN , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Cinética , Modelos Moleculares , Conformación Molecular , Niacinamida/química , Relación Estructura-ActividadRESUMEN
We have developed a series of cyclic amine-containing benzimidazole carboxamide PARP inhibitors with a methyl-substituted quaternary center at the point of attachment to the benzimidazole ring system. These compounds exhibit excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a K(i) of 5 nM and in a C41 whole cell assay with an EC(50) of 2 nM. In addition, 3a is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast cancer xenograft model in combination with either carboplatin or cyclophosphamide.
Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Melanoma Experimental/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Área Bajo la Curva , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Disponibilidad Biológica , Carboplatino/administración & dosificación , Ciclofosfamida/administración & dosificación , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Femenino , Haplorrinos , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Ratones SCID , Ratas , TemozolomidaRESUMEN
ABT-888 is a potent, orally bioavailable PARP-1/2 inhibitor shown to potentiate DNA damaging agents. The ability to potentiate temozolomide (TMZ) and develop a biological marker for PARP inhibition was evaluated in vivo. Doses/schedules that achieve TMZ potentiation in the B16F10 syngeneic melanoma model were utilized to develop an ELISA to detect a pharmacodynamic marker, ADP ribose polymers (pADPr), after ABT 888 treatment. ABT-888 enhanced TMZ antitumor activity, in a dose-proportional manner with no observed toxicity (44-75% tumor growth inhibition vs. TMZ monotherapy), but did not show single agent activity. Extended ABT-888 dosing schedules showed no advantage compared to simultaneous TMZ administration. Efficacy correlated with plasma/tumor drug concentrations. Intratumor drug levels correlated with a dose-proportional/time-dependent reduction in pADPr. Potentiation of TMZ activity by ABT-888 correlated with drug levels and inhibition of PARP activity in vivo. ABT-888 is in Phase 1 trials using a validated ELISA based on the assay developed here to assess pharmacological effect.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bencimidazoles/farmacología , Dacarbazina/análogos & derivados , Melanoma Experimental/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Dacarbazina/administración & dosificación , Dacarbazina/farmacocinética , Dacarbazina/farmacología , Esquema de Medicación , Sinergismo Farmacológico , Melanoma Experimental/enzimología , Melanoma Experimental/metabolismo , Ratones , Poli Adenosina Difosfato Ribosa/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , TemozolomidaRESUMEN
7-Aminopyrazolo[1,5- a]pyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure-activity relationships of the pyrazolo[1,5- a]pyrimidine nucleus led to a series of 6-(4- N, N'-diphenyl)ureas that potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases. Several of these compounds, such as 34a, are potent inhibitors of kinase insert domain-containing receptor tyrosine kinase (KDR) both enzymatically (<10 nM) and cellularly (<10 nM). In addition, compound 34a possesses a favorable pharmacokinetic profile and demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model (ED 50 = 1.4 mg/kg).
Asunto(s)
Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Edema/tratamiento farmacológico , Edema/enzimología , Femenino , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Compuestos de Fenilurea/química , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/química , Pirazoles/uso terapéutico , Pirimidinas/química , Pirimidinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/química , Relación Estructura-Actividad , Urea/química , Enfermedades Uterinas/tratamiento farmacológico , Enfermedades Uterinas/enzimologíaRESUMEN
We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Melanoma Experimental/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/uso terapéutico , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Ratones , Relación Estructura-Actividad , Temozolomida , Trasplante Heterólogo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of benzoisoxazoles and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure-activity relationship studies led to the identification of 3-amino benzo[ d]isoxazoles, incorporating a N, N'-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compounds possessing promising pharmacokinetic profiles were identified, and a number of compounds demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, compound 50 exhibited an ED 50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.
Asunto(s)
Isoxazoles/síntesis química , Modelos Moleculares , Oxazoles/síntesis química , Compuestos de Fenilurea/síntesis química , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Sitios de Unión , Disponibilidad Biológica , Permeabilidad Capilar/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Edema/tratamiento farmacológico , Femenino , Humanos , Isoxazoles/farmacocinética , Isoxazoles/farmacología , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Oxazoles/farmacocinética , Oxazoles/farmacología , Compuestos de Fenilurea/farmacocinética , Compuestos de Fenilurea/farmacología , Fosforilación , Relación Estructura-Actividad , Útero/irrigación sanguínea , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Tumor angiogenesis is mediated by KDR and other VEGFR and PDGFR kinases. Their inhibition presents an attractive approach for developing anticancer therapeutics. Here, we report a series of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors. A number of compounds have been identified to be orally bioavailable and efficacious in the mouse edema model.
Asunto(s)
Aminopiridinas/química , Aminopiridinas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Urea/análogos & derivados , Administración Oral , Aminopiridinas/síntesis química , Aminopiridinas/farmacocinética , Animales , Disponibilidad Biológica , Edema/tratamiento farmacológico , Edema/metabolismo , Femenino , Concentración 50 Inhibidora , Ratones , Modelos Moleculares , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/farmacología , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacología , Enfermedades Uterinas/tratamiento farmacológico , Enfermedades Uterinas/metabolismoRESUMEN
A novel series of 5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-ones have been synthesized as potent and selective checkpoint kinase 1 (Chk1) inhibitors via structure-based design. Aided by protein X-ray crystallography, medicinal chemistry efforts led to the identification of compound 46d, with potent enzymatic activity against Chk1 kinase. While maintaining a low cytotoxicity of its own, compound 46d exhibited a strong ability to abrogate G2 arrest and increased the cytotoxicity of camptothecin by 19-fold against SW620 cells. Pharmacokinetic studies revealed that it had a moderate bioavailabilty of 20% in mice. Two important binding interactions between compound 46b and Chk1 kinase, revealed by X-ray cocrystal structure, were hydrogen bonds between the hinge region and the amide bond of the core structure and a hydrogen bond between the methoxy group and Lys38 of the protein.
Asunto(s)
Antineoplásicos/síntesis química , Azepinas/síntesis química , Benzodiazepinonas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Quinasas/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Azepinas/química , Azepinas/farmacología , Benzodiazepinonas/química , Benzodiazepinonas/farmacología , Disponibilidad Biológica , Camptotecina/farmacología , Línea Celular Tumoral , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Cristalografía por Rayos X , Doxorrubicina/farmacología , Diseño de Fármacos , Sinergismo Farmacológico , Humanos , Ratones , Modelos Moleculares , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
PURPOSE: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888. EXPERIMENTAL DESIGN: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation. RESULTS: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with K(i)s of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d x 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity. CONCLUSIONS: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
Asunto(s)
Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Administración Oral , Animales , Antineoplásicos Alquilantes/uso terapéutico , Disponibilidad Biológica , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Daño del ADN , Modelos Animales de Enfermedad , Perros , Sinergismo Farmacológico , Femenino , Haplorrinos , Humanos , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Endogámicas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.
Asunto(s)
Alquinos/síntesis química , Antineoplásicos/síntesis química , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Indenos/síntesis química , Pirazoles/síntesis química , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tiofenos/síntesis química , Alquinos/efectos adversos , Alquinos/farmacología , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Unión Competitiva , Línea Celular , Canal de Potasio ERG1 , Edema/inducido químicamente , Edema/tratamiento farmacológico , Estradiol , Canales de Potasio Éter-A-Go-Go/fisiología , Femenino , Humanos , Indenos/efectos adversos , Indenos/farmacología , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Técnicas de Placa-Clamp , Unión Proteica , Pirazoles/efectos adversos , Pirazoles/metabolismo , Pirazoles/farmacología , Ensayo de Unión Radioligante , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/metabolismo , Tiofenos/farmacología , Enfermedades Uterinas/inducido químicamente , Enfermedades Uterinas/tratamiento farmacológico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N'-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.