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
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
N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N1-(2-fluoro-5-methyl phenyl)-urea (ABT-869) is a novel multitargeted receptor tyrosine kinase inhibitor that demonstrates single-agent activity in preclinical studies and has undergone phase I and II clinical trials. We characterized the mechanism of action of ABT-869 by examining vascular changes after treatment (25 mg/kg per day) in HT1080 fibrosarcoma and SW620 colon carcinoma cells, using immunohistochemistry, dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI), and hypoxic protein detection. We observed the inhibition of vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor ß phosphorylation in both tumors and changes in tumor vasculature. Reductions in microvessel density and diameter were observed. Vascular-wall integrity was assessed by colocalization of pericytes and basement membrane. Although both microvessel density and total number of pericytes decreased with treatment, the percentage of pericyte coverage on remaining vessels significantly increased. These data suggest the selective ablation of microvessels lacking pericyte coverage. Functional vascular measures DCE-MRI and hypoxia formation were also tested. After 2 days of treatment on the HT1080 model, vascular permeability, K(trans), was reduced by >60% and hypoxic tumor fraction was significantly decreased, which was also seen in the SW620 tumors after 4 days of treatment. Taken together, decreases in vascular permeability and changes in vascular integrity observed in these studies define the mode of action of ABT-869 and may aid in optimizing the timing of therapeutic window for combination therapies.
Asunto(s)
Permeabilidad Capilar/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Indazoles/farmacología , Indazoles/uso terapéutico , Neovascularización Patológica/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Permeabilidad Capilar/fisiología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos/métodos , Endotelio Vascular/metabolismo , Humanos , Ratones , Neovascularización Patológica/enzimología , Neovascularización Patológica/patología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea] is a novel multitargeted inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase family members. ABT-869 demonstrates tumor growth inhibition in multiple preclinical animal models and in early clinical trials. VEGF receptor inhibition is also associated with reversible hypertension that may limit its benefit clinically. To evaluate optimal therapeutic approaches to prevent hypertension with VEGF receptor inhibition, we characterized the dose-dependent effects of seven antihypertensive agents from three mechanistic classes [angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs)] on hypertension induced by ABT-869 in conscious telemetry rats. We report that ABT-869-induced hypertension can be prevented and reversed with subtherapeutic or therapeutic doses of antihypertensive drugs with a general rank order of ACEi > ARB > CCB. In SCID mice, the ACE inhibitor, enalapril (C(20)H(28)N(2)O(5) x C(4)H(4)O(4)) at 30 mg/kg, prevented hypertension, with no attenuation of the antitumor efficacy of ABT-869. These studies demonstrate that the adverse cardiovascular effects of the VEGF/PDGF receptor tyrosine kinase inhibitor, ABT-869, are readily controlled by conventional antihypertensive therapy without affecting antitumor efficacy.
Asunto(s)
Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Indazoles/farmacología , Neoplasias/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Acrilatos/farmacología , Amlodipino/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Bencimidazoles/farmacología , Benzoatos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Relación Dosis-Respuesta a Droga , Enalapril/farmacología , Humanos , Imidazoles/farmacología , Indazoles/efectos adversos , Indazoles/uso terapéutico , Lisinopril/farmacología , Masculino , Ratones , Ratones SCID , Neoplasias/patología , Nifedipino/farmacología , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/uso terapéutico , Ramipril/farmacología , Ratas , Ratas Sprague-Dawley , Telmisartán , Tiofenos/farmacología , 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.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Indazoles/síntesis química , Compuestos de Fenilurea/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Adenosina Trifosfato/química , Administración Oral , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Sitios de Unión , Edema/inducido químicamente , Edema/patología , Estradiol , Femenino , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Indazoles/química , Indazoles/farmacología , Masculino , Ratones , Modelos Moleculares , Células 3T3 NIH , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Fosforilación , Proteínas Tirosina Quinasas Receptoras/química , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Útero/efectos de los fármacos , Útero/patología , 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
Polo-like kinase 1 (Plk1) is required for multiple stages of mitosis and is up-regulated in many human malignancies. We depleted Plk1 expression using small interfering RNA (siRNA) and showed defects in bipolar spindle formation and cytokinesis, growth inhibition, and apoptosis induction in human cancer cell lines. To our surprise, depletion of Plk1 in normal human cells did not result in obvious cell cycle defects, and did not induce significant inhibition of cell growth for at least two cell cycles. In addition, Plk1 siRNA inhibited colony formation in soft agar and tumorigenesis in a HT1080 xenograft model in a dose-dependent manner. Analysis with isogenic pairs of cell lines, differing in p53 status, revealed that Plk1 depletion preferentially induced mitotic arrest, aneuploidy, and reduced cell survival in the p53-defective cell lines. No obvious defects were observed in most p53 wild-type cells during the first few cell cycles. In addition, long-term survival studies revealed that p53 facilitates survival upon Plk1 depletion. Therefore, short-term inhibition of Plk1 can kill tumor cells while allowing normal cells to survive. These data validate the episodic inhibition of Plk1 as a very useful approach for cancer treatment.
Asunto(s)
Transformación Celular Neoplásica/patología , Proteínas Quinasas/deficiencia , Proteínas Proto-Oncogénicas/deficiencia , ARN Interferente Pequeño/genética , Proteína p53 Supresora de Tumor/genética , Animales , Apoptosis/genética , Apoptosis/fisiología , Ciclo Celular/genética , Ciclo Celular/fisiología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Fibrosarcoma/genética , Fibrosarcoma/patología , Fibrosarcoma/terapia , Humanos , Ratones , Ratones SCID , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Transfección , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasa Tipo Polo 1RESUMEN
ABT-869 is a structurally novel, receptor tyrosine kinase (RTK) inhibitor that is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor families (e.g., KDR IC50 = 4 nmol/L) but has much less activity (IC50s > 1 micromol/L) against unrelated RTKs, soluble tyrosine kinases, or serine/threonine kinases. The inhibition profile of ABT-869 is evident in cellular assays of RTK phosphorylation (IC50 = 2, 4, and 7 nmol/L for PDGFR-beta, KDR, and CSF-1R, respectively) and VEGF-stimulated proliferation (IC50 = 0.2 nmol/L for human endothelial cells). ABT-869 is not a general antiproliferative agent because, in most cancer cells, >1,000-fold higher concentrations of ABT-869 are required for inhibition of proliferation. However, ABT-869 exhibits potent antiproliferative and apoptotic effects on cancer cells whose proliferation is dependent on mutant kinases, such as FLT3. In vivo ABT-869 is effective orally in the mechanism-based murine models of VEGF-induced uterine edema (ED50 = 0.5 mg/kg) and corneal angiogenesis (>50% inhibition, 15 mg/kg). In tumor growth studies, ABT-869 exhibits efficacy in human fibrosarcoma and breast, colon, and small cell lung carcinoma xenograft models (ED50 = 1.5-5 mg/kg, twice daily) and is also effective (>50% inhibition) in orthotopic breast and glioma models. Reduction in tumor size and tumor regression was observed in epidermoid carcinoma and leukemia xenograft models, respectively. In combination, ABT-869 produced at least additive effects when given with cytotoxic therapies. Based on pharmacokinetic analysis from tumor growth studies, efficacy correlated more strongly with time over a threshold value (cellular KDR IC50 corrected for plasma protein binding = 0.08 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Indazoles/farmacología , Compuestos de Fenilurea/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Células 3T3 , Animales , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Córnea , Edema , Femenino , Ratones , Neovascularización Fisiológica/efectos de los fármacos , Fosforilación , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptores de Factores de Crecimiento Endotelial Vascular/metabolismo , Vasos Retinianos/efectos de los fármacos , Vasos Retinianos/fisiología , Útero/efectos de los fármacos , Útero/fisiopatologíaRESUMEN
Methionine aminopeptidase (MetAP)-2 has been suggested as a novel target for cancer therapy because the anticancer agent TNP-470 irreversibly inactivates the catalytic activity of this enzyme. However, the importance of MetAP2 in cell growth and tumor progression was uncertain because previous data were based on the chemically reactive TNP-470. Here we show that a rationally designed reversible MetAP2 inhibitor, A-357300, suppresses tumor growth preclinically without the toxicities observed with TNP-470. We have synthesized this bestatin-type MetAP2 inhibitor with the aid of crystal structures of the enzyme-inhibitor complexes and parallel synthesis. A-357300 induces cytostasis by cell cycle arrest at the G(1) phase selectively in endothelial cells and in a subset of tumor cells, but not in most primary cells of nonendothelial type. A-357300 inhibits angiogenesis both in vitro and in vivo and shows potent antitumor efficacy in carcinoma, sarcoma, and neuroblastoma murine models. These data affirm that MetAP2 plays a pivotal role in cell growth and establish that reversible MetAP2 inhibitors are promising novel cancer therapeutic agents.
Asunto(s)
Aminopeptidasas/antagonistas & inhibidores , Antineoplásicos/farmacología , Clorobencenos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/toxicidad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Clorobencenos/química , Clorobencenos/toxicidad , Córnea/irrigación sanguínea , Ciclohexanos , Diseño de Fármacos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Femenino , Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/enzimología , Humanos , Ratones , Ratones SCID , Modelos Moleculares , Neovascularización Fisiológica/efectos de los fármacos , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/enzimología , O-(Cloroacetilcarbamoil) Fumagilol , Inhibidores de Proteasas/química , Inhibidores de Proteasas/toxicidad , Sesquiterpenos/química , Sesquiterpenos/farmacología , Sesquiterpenos/toxicidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BCL-2 family proteins dictate survival of human multiple myeloma cells, making them attractive drug targets. Indeed, multiple myeloma cells are sensitive to antagonists that selectively target prosurvival proteins such as BCL-2/BCL-XL (ABT-737 and ABT-263/navitoclax) or BCL-2 only (ABT-199/GDC-0199/venetoclax). Resistance to these three drugs is mediated by expression of MCL-1. However, given the selectivity profile of venetoclax it is unclear whether coexpression of BCL-XL also affects antitumor responses to venetoclax in multiple myeloma. In multiple myeloma cell lines (n = 21), BCL-2 is expressed but sensitivity to venetoclax correlated with high BCL-2 and low BCL-XL or MCL-1 expression. Multiple myeloma cells that coexpress BCL-2 and BCL-XL were resistant to venetoclax but sensitive to a BCL-XL-selective inhibitor (A-1155463). Multiple myeloma xenograft models that coexpressed BCL-XL or MCL-1 with BCL-2 were also resistant to venetoclax. Resistance to venetoclax was mitigated by cotreatment with bortezomib in xenografts that coexpressed BCL-2 and MCL-1 due to upregulation of NOXA, a proapoptotic factor that neutralizes MCL-1. In contrast, xenografts that expressed BCL-XL, MCL-1, and BCL-2 were more sensitive to the combination of bortezomib with a BCL-XL selective inhibitor (A-1331852) but not with venetoclax cotreatment when compared with monotherapies. IHC of multiple myeloma patient bone marrow biopsies and aspirates (n = 95) revealed high levels of BCL-2 and BCL-XL in 62% and 43% of evaluable samples, respectively, while 34% were characterized as BCL-2(High)/BCL-XL (Low) In addition to MCL-1, our data suggest that BCL-XL may also be a potential resistance factor to venetoclax monotherapy and in combination with bortezomib. Mol Cancer Ther; 15(5); 1132-44. ©2016 AACR.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/genética , Sulfonamidas/farmacología , Proteína bcl-X/genética , Animales , Proteína 11 Similar a Bcl2/metabolismo , Bortezomib/farmacología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/genética , Quimioterapia Combinada , Humanos , Inmunohistoquímica , Ratones , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of novel thienopyrimidine-based receptor tyrosine kinase inhibitors has been discovered. Investigation of structure-activity relationships at the 5- and 6-positions of the thienopyrimidine nucleus led to a series of N,N'-diaryl ureas that potently inhibit all of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinases. A kinase insert domain-containing receptor (KDR) homology model suggests that these compounds bind to the "inactive conformation" of the enzyme with the urea portion extending into the back hydrophobic pocket adjacent to the adenosine 5'-triphosphate (ATP) binding site. A number of compounds have been identified as displaying excellent in vivo potency. In particular, compounds 28 and 76 possess favorable pharmacokinetic (PK) profiles and demonstrate potent antitumor efficacy against the HT1080 human fibrosarcoma xenograft tumor growth model (tumor growth inhibition (TGI) = 75% at 25 mg/kg.day, per os (po)).
Asunto(s)
Antineoplásicos/síntesis química , Pirimidinas/síntesis química , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Urea/análogos & derivados , Urea/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adenosina Trifosfato/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Edema/inducido químicamente , Edema/patología , Estradiol , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Modelos Moleculares , Células 3T3 NIH , Fosforilación , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Urea/química , Urea/farmacología , Útero/efectos de los fármacos , Útero/patología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
Asunto(s)
Antineoplásicos/síntesis química , Formamidas/síntesis química , Hidroxilaminas/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular , Formamidas/química , Formamidas/farmacocinética , Formamidas/farmacología , Hidroxilaminas/química , Hidroxilaminas/farmacocinética , Hidroxilaminas/farmacología , Macaca fascicularis , Inhibidores de la Metaloproteinasa de la Matriz , Ratones , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Linifanib (ABT-869) is a multitargeted receptor tyrosine kinase inhibitor. This work aims to evaluate F-fluorodeoxyglucose-positron emission tomography (FDG-PET) as a pharmacodynamic (PD) biomarker for linifanib treatment utilizing the Calu-6 model of human non-small cell lung (NSCLC) cancer in SCID-beige mice. Animals received either vehicle or 12.5 mg/kg linifanib orally twice a day for the duration of the study. Imaging was performed at -1, 1, 3, and 7 days after beginning treatment (n = 12-14 per group). Linifanib inhibited tumor growth and suppressed tumor metabolic activity. Changes in tumor FDG uptake were observed as early as 1 day after beginning linifanib treatment and were sustained for the duration of the study. This study confirms that linifanib is efficacious in this xenograft model of human NSCLC and confirms FDG-PET is a potential PD biomarker strategy for linifanib therapy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Fluorodesoxiglucosa F18 , Indazoles/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Tomografía de Emisión de Positrones , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Ratones , Ratones SCID , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Longitudinal changes of 3'-[(18) F]fluoro-3'-deoxythymidine (FLT) and 2-deoxy-2-[(18) F]fluoro-D-glucose (FDG) in response to irinotecan therapy in an animal model of colorectal cancer were compared. PROCEDURES: SCID/CB-17 mice with HCT116 tumors were treated with 50 mg/kg irinotecan by intraperitoneal injection weekly for 3 weeks. FLT and FDG-positron emission tomography (PET) were performed at baseline, the day after each treatment, and 5 days after the first treatment. Proliferation and apoptosis were evaluated by immunohistochemistry (IHC) after day 15 of imaging. RESULTS: Irinotecan treatment resulted in a suppression of tumor growth. Tumor FLT uptake was decreased the day after each treatment but to a lesser extent 5 days after the first treatment. FDG uptake increased the day after each treatment with a continuous increase throughout the experiment. IHC analysis of phospho-H3 and Ki67 confirmed FLT-PET results, indicating a decrease in proliferation the day after the final irinotecan treatment. Increased apoptosis monitored by caspase-3 was observed after day 15 with irinotecan treatment. CONCLUSIONS: FLT-PET may be a better method than FDG-PET for assessing treatment response to irinotecan. Changes in imaging occur before changes in tumor volume.
Asunto(s)
Camptotecina/análogos & derivados , Neoplasias Colorrectales/diagnóstico por imagen , Neoplasias Colorrectales/tratamiento farmacológico , Didesoxinucleósidos , Fluorodesoxiglucosa F18 , Imagen Multimodal , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Camptotecina/farmacología , Camptotecina/uso terapéutico , Línea Celular Tumoral , Neoplasias Colorrectales/patología , Didesoxinucleósidos/farmacocinética , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Inmunohistoquímica , Irinotecán , Ratones , Ratones SCID , Carga TumoralRESUMEN
In 15% to 30% of patients with acute myeloid leukemia (AML), aberrant proliferation is a consequence of a juxtamembrane mutation in the FLT3 gene (FMS-like tyrosine kinase 3-internal tandem duplication [FLT3-ITD]), causing constitutive kinase activity. ABT-869 (a multitargeted receptor tyrosine kinase inhibitor) inhibited the phosphorylation of FLT3, STAT5, and ERK, as well as Pim-1 expression in MV-4-11 and MOLM-13 cells (IC(50) approximately 1-10 nM) harboring the FLT3-ITD. ABT-869 inhibited the proliferation of these cells (IC(50) = 4 and 6 nM, respectively) through the induction of apoptosis (increased sub-G(0)/G(1) phase, caspase activation, and PARP cleavage), whereas cells harboring wild-type (wt)-FLT3 were less sensitive. In normal human blood spiked with AML cells, ABT-869 inhibited phosphorylation of FLT3 (IC(50) approximately 100 nM), STAT5, and ERK, and decreased Pim-1 expression. In methylcellulose-based colony-forming assays, ABT-869 had no significant effect up to 1000 nM on normal hematopoietic progenitor cells, whereas in AML patient samples harboring both FLT3-ITD and wt-FLT3, ABT-869 inhibited colony formation (IC(50) = 100 and 1000 nM, respectively). ABT-869 dose-dependently inhibited MV-4-11 and MOLM-13 flank tumor growth, prevented tumor formation, regressed established MV-4-11 xenografts, and increased survival by 20 weeks in an MV-4-11 engraftment model. In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML.
Asunto(s)
Indazoles/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fase G1/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Células K562 , Antígeno Ki-67/biosíntesis , Leucemia Mieloide Aguda/enzimología , Ratones , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-pim-1 , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Factor de Transcripción STAT5/metabolismo , Ensayo de Tumor de Célula Madre , Células U937RESUMEN
A series of hydroxamic acid-based HDAC inhibitors with an indole amide residue at the terminus have been synthesized and evaluated. Compounds with a 2-indole amide moiety have been found as the most active inhibitors among the different regioisomers. Introduction of substituents on the indole ring further improved the potency and generated a series of very potent inhibitors with significant antiproliferative activity. A representative compound in the series, 7b, has been found to be orally active in tumor growth inhibition model.
Asunto(s)
Amidas/química , Amidas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/farmacología , Indoles/química , Indoles/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Humanos , Ácidos Hidroxámicos/química , Concentración 50 Inhibidora , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Alpha-keto ester and amides were found to be potent inhibitors of histone deacetylase. Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model.