RESUMEN
AIMS: Endothelin receptor A (ET(A)) antagonism normalizes fetal growth in several models of rodent fetal growth restriction (FGR). Our aims were to determine the levels of ET(A) antagonist in maternal and fetal plasma following chronic maternal administration, and to determine its impact on pregnancy outcome, survival and growth of rat pups. MAIN METHODS: Timed pregnant rats were treated with one of two endothelin receptor antagonists or vehicle, from gestation day 14-21 (term=22 days). The antagonists and their respective doses were ABT-546 (20mg/kg/day) and FR139317 (12 mg/kg/day). On day 21, in six rats per group, maternal and fetal plasma ABT-546 was assayed by HPLC. Five additional rats in each group delivered spontaneously and nursed their pups through postpartum day 7. Viability of newborns, oxygen saturation, litter sizes, and pup weights were recorded on postpartum days 1 and 7. KEY FINDINGS: Fetal antagonist levels reached only 2% of maternal levels (p<0.01). There were no significant differences among groups in length of gestation; litter size; survival, number and weight of live pups at birth and at 7 days postpartum; and tissue oxygen saturation. SIGNIFICANCE: Maternal administration of an ET(A) antagonist, at a dose sufficient to ameliorate FGR, has no adverse impact on survival and growth of neonatal rat pups. ET(A) antagonism, delivered maternally, produces sufficiently low fetal plasma levels of antagonist so as not to present a survival threat to the neonatal pups. The beneficial effects of maternally administered ET(A) antagonism on fetal growth occur in the maternal, not the fetal, compartment.
Asunto(s)
Azepinas/farmacología , Antagonistas de los Receptores de la Endotelina A , Desarrollo Fetal/efectos de los fármacos , Indoles/farmacología , Pirrolidinas/farmacología , Animales , Animales Recién Nacidos , Azepinas/administración & dosificación , Azepinas/farmacocinética , Femenino , Retardo del Crecimiento Fetal/prevención & control , Indoles/administración & dosificación , Indoles/farmacocinética , Intercambio Materno-Fetal , Embarazo , Resultado del Embarazo , Pirrolidinas/administración & dosificación , Pirrolidinas/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
1. It has been shown that tubulin-binding agents can destabilize cellular microtubules and suppress tumour growth; but it has also become apparent that some compounds can exert anti-vascular effects within the neovasculature of a solid tumour. To date, the difficulty with these targets has been the ability to selectivity induce vascular damage to the tumour while leaving normal vasculature unaffected. The data presented here characterizes the in vivo, tumour selective, anti-vascular effects of the novel tubulin-binding agent A-318315. 2. To that purpose, we have used an anaesthetized in vivo rat model designed to quantify acute changes in regional vascular resistance (VR) in both tumour and non-tumour vascular beds, simultaneously. Tissue-isolated tumours (approximately 1.25 gm) with blood flow supplied by a single epigastric artery were grown in the hindlimb of adult male rats. Blood flow to the tumour, mesenteric, renal and normal (non-tumour epigastric) arteries was measured pre-dose and post-dose under anaesthesia. 3. A-318315 was tested at 3, 10 and 30 mg/kg, i.v. These doses produced modest, transient increases in mean arterial pressure with little to no effect on heart rate. At peak effect, tumour VR increased to 175 +/- 47, 337 +/- 77 and 751 +/- 151% above the baseline, for the 3, 10 and 30 mg/kg doses, respectively, whereas VR was only modestly and transiently increased in normal epigastric (88 +/- 19%), mesenteric (33 +/- 3.3%) and renal arteries (17 +/- 8.6%). 4. These data demonstrate that A-318315 produces marked reductions in tumour blood flow in the rat at doses that exert minor effects on normal vascular function.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antimitóticos/uso terapéutico , Hemodinámica/efectos de los fármacos , Indoles/uso terapéutico , Neovascularización Patológica/tratamiento farmacológico , Sulfonamidas/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Antimitóticos/efectos adversos , Antimitóticos/farmacocinética , Antimitóticos/farmacología , Presión Sanguínea/efectos de los fármacos , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Indoles/efectos adversos , Indoles/farmacocinética , Indoles/farmacología , Masculino , Estructura Molecular , Neovascularización Patológica/metabolismo , Neovascularización Patológica/fisiopatología , Ratas , Ratas Endogámicas F344 , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Tubulina (Proteína)/metabolismo , Resistencia Vascular/efectos de los fármacosRESUMEN
PURPOSE: ABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF penetration. METHODS: ABT-888, 5 mg/kg, was administered orally to three NHPs. Serial blood and CSF samples were obtained. Plasma and CSF concentrations of ABT-888 were measured using LC/MS/MS, and the resulting concentration versus time data were evaluated using non-compartmental and compartmental PK methods. RESULTS: The CSF penetration of ABT-888 was 57+/-7% (mean+/-SD). The peak ABT-888 concentration in the plasma was 0.62+/-0.18 microM. Plasma and CSF AUC0-infinity were 3.7+/-1.7 and 2.1+/-0.8 microM h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration. CONCLUSION: The CSF penetration of ABT-888 after oral administration was 57%. Plasma and CSF concentrations were in the range that has been shown to inhibit PARP activity in vivo in humans.
Asunto(s)
Bencimidazoles/sangre , Bencimidazoles/líquido cefalorraquídeo , Administración Oral , Animales , Área Bajo la Curva , Bencimidazoles/farmacocinética , Humanos , Leucocitos Mononucleares/enzimología , Macaca mulatta , Masculino , Tasa de Depuración Metabólica , Estructura Molecular , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Poli(ADP-Ribosa) Polimerasas/metabolismo , Factores de TiempoRESUMEN
ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-x(L), and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a macrolide antibiotic that inhibits the mammalian target of rapamycin complex, leading to cell cycle arrest and inhibition of protein translation. Rapamycin (and its analogues) has shown activity in a variety of tumor cell lines primarily through induction of cell cycle arrest. Activity has also been shown clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100 nmol/L rapamycin induces substantial G(0)-G(1) arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G(0) cells. Combination of these agents also led to a significant increase in Annexin V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models. Coadministration with ABT-263 induced significant tumor regression, with DoHH-2 and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these tumors was significantly enhanced by combination therapy as measured by staining with an antibody specific for cleaved caspase-3. These data suggest that combination of ABT-263 and rapamycin or its analogues represents a promising therapeutic strategy for the treatment of lymphoma.
Asunto(s)
Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Linfoma de Células B Grandes Difuso/patología , Sirolimus/farmacología , Sulfonamidas/farmacología , Animales , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Inmunohistoquímica , Linfoma de Células B Grandes Difuso/terapia , Ratones , Ratones SCID , Inducción de Remisión , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC 50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.
Asunto(s)
Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Administración Oral , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Estructura Molecular , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models. EXPERIMENTAL DESIGN: A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison to standard cytotoxic agents, and induction of apoptosis. RESULTS: ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic schedules and was associated with significant induction of apoptosis. CONCLUSIONS: ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent.
Asunto(s)
Compuestos de Anilina/administración & dosificación , Antineoplásicos/administración & dosificación , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Ratones Desnudos , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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
Sirolimus (rapamycin) is an immunosuppressant used in preventing allograft rejection and in drug-eluting stents to prevent restenosis after angioplasty. Zotarolimus, an analogue of sirolimus, was designed to have a shorter in vivo half-life. Zotarolimus was found to be mechanistically similar to sirolimus in having high-affinity binding to the immunophilin FKBP12 and comparable potency for inhibiting in vitro proliferation of both human and rat T cells. Rat pharmacokinetic studies with intravenous dosing demonstrated terminal elimination half-lives of 9.4 hours and 14.0 hours for zotarolimus and sirolimus, respectively. Given orally, T1/2 values were 7.9 hours and 33.4 hours, respectively. Consistent with its shorter duration, zotarolimus showed a corresponding and statistically significant 4-fold reduction in potency for systemic immunosuppression in 3 rat disease models. Pharmacokinetic studies in cynomolgus monkey underpredicted the half-life difference between zotarolimus and sirolimus apparent from recent clinical data. In vitro inhibition of human coronary artery smooth muscle cell proliferation by zotarolimus was comparable to sirolimus. Drug-eluting stents for local delivery of zotarolimus to the vessel wall of coronary arteries are in clinical development. The pharmacological profile of zotarolimus suggests it may be advantageous for preventing restenosis with a reduced potential for causing systemic immunosuppression or other side effects.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Vasos Coronarios/citología , Rechazo de Injerto/prevención & control , Inmunosupresores/farmacología , Miocitos del Músculo Liso/efectos de los fármacos , Sirolimus/análogos & derivados , Animales , Animales Recién Nacidos , Unión Competitiva/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/prevención & control , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/prevención & control , Semivida , Trasplante de Corazón , Humanos , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/prevención & control , Inmunosupresores/efectos adversos , Inmunosupresores/sangre , Inmunosupresores/farmacocinética , Concentración 50 Inhibidora , Prueba de Cultivo Mixto de Linfocitos , Masculino , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Sirolimus/efectos adversos , Sirolimus/sangre , Sirolimus/farmacocinética , Sirolimus/farmacología , Linfocitos T/efectos de los fármacos , Proteína 1A de Unión a Tacrolimus/efectos de los fármacosRESUMEN
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
PURPOSE: ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on beta-tubulin and inhibits microtubule polymerization. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of ABT-751, after a short intravenous infusion, were evaluated in a non-human primate (Macaca mulatta) model that is highly predictive of the CSF penetration of drugs in humans. MATERIALS AND METHODS: Plasma and CSF samples were collected over 24 h after 7.5 mg/kg (150 mg/m2) ABT-751 infused over 0.25-0.70 h, and ABT-751 concentrations in plasma and CSF were quantified using a validated HPLC-MS/MS assay. Pharmacokinetic parameters in plasma and CSF were derived using non-compartmental methods. RESULTS AND CONCLUSION: Plasma disappearance was bi-exponential with a terminal half-life of 13 h. The mean +/- SD clearance was 100 +/- 18 ml/min m2, the mean +/- SD volume of distribution at steady state was 1.3 +/- 0.5 l/kg, and the mean +/- SD mean residence time was 4.6 +/- 1.8 h. The mean +/- SD peak ABT-751 concentration in CSF was 0.26 +/- 0.08 microM, and the mean +/- SD CSF half-life of 1.3 +/- 0.3 h. CSF penetration was limited (mean +/- SD AUC(CSF):AUC(plasma), 1.1 +/- 0.3%) relative to total (protein-bound + free) plasma drug concentrations, but the CSF concentrations approximated the estimated free drug concentrations in plasma.
Asunto(s)
Sulfonamidas/sangre , Sulfonamidas/líquido cefalorraquídeo , Animales , Infusiones Intravenosas , Macaca mulattaRESUMEN
Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-X(L) versus Bcl-2 (K(i)'s of 0.80 and 67 nmol/L for Bcl-X(L) and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC(50) of <500 nmol/L in cells dependent on Bcl-X(L) for survival. In addition, A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (paclitaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines. In A549 non-small-cell lung cancer cells, A-385358 potentiates the activity of paclitaxel by as much as 25-fold. Importantly, A-385358 also potentiated the activity of paclitaxel in vivo. Significant inhibition of tumor growth was observed when A-385358 was added to maximally tolerated or half maximally tolerated doses of paclitaxel in the A549 xenograft model. In tumors, the combination therapy also resulted in a significant increase in mitotic arrest followed by apoptosis relative to paclitaxel monotherapy.
Asunto(s)
Compuestos de Anilina/farmacología , Antineoplásicos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Nitrofenoles/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Proteína bcl-X/antagonistas & inhibidores , Compuestos de Anilina/farmacocinética , Compuestos de Anilina/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Compuestos de Bifenilo/farmacocinética , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Cinética , Masculino , Ratones , Ratones SCID , Nitrofenoles/farmacocinética , Nitrofenoles/farmacología , Paclitaxel/farmacocinética , Piperazinas/farmacocinética , Piperazinas/farmacología , Piperazinas/uso terapéutico , Sulfonamidas/farmacocinética , Trasplante HeterólogoRESUMEN
Hutchinson-Gilford progeria syndrome (HGPS) is caused by the production of a truncated prelamin A, called progerin, which is farnesylated at its carboxyl terminus. Progerin is targeted to the nuclear envelope and causes misshapen nuclei. Protein farnesyltransferase inhibitors (FTI) mislocalize progerin away from the nuclear envelope and reduce the frequency of misshapen nuclei. To determine whether an FTI would ameliorate disease phenotypes in vivo, we created gene-targeted mice with an HGPS mutation (LmnaHG/+) and then examined the effect of an FTI on disease phenotypes. LmnaHG/+ mice exhibited phenotypes similar to those in human HGPS patients, including retarded growth, reduced amounts of adipose tissue, micrognathia, osteoporosis, and osteolytic lesions in bone. Osteolytic lesions in the ribs led to spontaneous bone fractures. Treatment with an FTI increased adipose tissue mass, improved body weight curves, reduced the number of rib fractures, and improved bone mineralization and bone cortical thickness. These studies suggest that FTIs could be useful for treating humans with HGPS.
Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Farnesiltransferasa/antagonistas & inhibidores , Progeria/genética , Animales , Enfermedades Óseas/diagnóstico por imagen , Huesos/diagnóstico por imagen , Modelos Animales de Enfermedad , Ratones , Mutación , Progeria/diagnóstico por imagen , Progeria/tratamiento farmacológico , RadiografíaRESUMEN
Development of a rationally designed potentiator of cancer chemotherapy, via inhibition of Bcl-X(L) function, is described. Lead compounds generated by NMR screening and directed parallel synthesis displayed sub-microM binding but were strongly deactivated in the presence of serum. The dominant component of serum deactivation was identified as domain III of human serum albumin (HSA); NMR solution structures of inhibitors bound to both Bcl-X(L) and HSA domain III indicated two potential optimization sites for separation of affinities. Modifications at both sites resulted in compounds with improved Bcl-X(L) binding and greatly increased activity in the presence of human serum, culminating in 73R, which bound to Bcl-X(L) with a K(i) of 0.8 nM. In a cellular assay 73R reversed the protection afforded by Bcl-X(L) overexpression against cytokine deprivation in FL5.12 cells with an EC(50) of 0.47 microM. 73R showed little effect on the viability of the human non small cell lung cancer cell line A549. However, consistent with the proposed mechanism, 73R potentiated the activity of paclitaxel and UV irradiation in vitro and potentiated the antitumor efficacy of paclitaxel in a mouse xenograft model.
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Compuestos de Anilina/síntesis química , Antineoplásicos/síntesis química , Piperidinas/síntesis química , Sulfonamidas/síntesis química , Proteína bcl-X/antagonistas & inhibidores , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Polarización de Fluorescencia , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Ratones SCID , Paclitaxel/farmacología , Piperidinas/química , Piperidinas/farmacología , Unión Proteica , Estructura Terciaria de Proteína , Suero , Albúmina Sérica/química , Estereoisomerismo , Sulfonamidas/química , Sulfonamidas/farmacología , Trasplante Heterólogo , Rayos UltravioletaRESUMEN
A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4'-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC(50) values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined.
Asunto(s)
Antineoplásicos , Inhibidores Enzimáticos , Etilenos , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Sitios de Unión , Proteínas Quinasas Dependientes de Calcio-Calmodulina/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Etilenos/síntesis química , Etilenos/farmacología , Glucógeno Sintasa Quinasa 3 , Humanos , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
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
PURPOSE: To evaluate the preclinical pharmacokinetics, antitumor efficacy, and mechanism of action of a novel orally active farnesyltransferase inhibitor, ABT-100. EXPERIMENTAL DESIGN: In vitro sensitivity of a panel of human cell lines was determined using proliferation and clonogenic assays. In vivo efficacy of ABT-100 was evaluated in xenograft models (flank or orthotopic) by assessing angiogenesis, proliferation, and apoptosis in correlation with pharmacokinetics. Efficacy of the racemate of ABT-100 (A-367074) was also compared with R115777 (tipifarnib). RESULTS: ABT-100 inhibited proliferation of cells in vitro carrying oncogenic H-Ras (EJ-1 bladder; IC(50) 2.2 nmol/L), Ki-Ras (DLD-1 colon, MDA-MB-231 breast, HCT-116 colon, and MiaPaCa-2 pancreatic; IC(50) range, 3.8-9.2 nmol/L), and wild-type Ras (PC-3 and DU-145; IC(50), 70 and 818 nmol/L, respectively) as well as clonogenic potential. ABT-100 shows 70% to 80% oral bioavailability in mice. ABT-100 regressed EJ-1 tumors (2-12.5 mg/kg/d s.c., every day for 21 days) and showed significant efficacy in DLD-1, LX-1, MiaPaCa-2, or PC-3 tumor-bearing mice (6.25-50 mg/kg/d s.c. once daily or twice daily orally). A-367074 showed equivalent efficacy to R115777 given at approximately one-fourth the total dose of R115777 for a shorter duration (EJ-1 and LX-1). Antitumor activity was associated with decreased cell proliferation (Ki-67), increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), and decreased angiogenesis. A reduction in tumor angiogenic cytokine levels (vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8) correlated with a reduction in tumor vascularity (CD31). CONCLUSIONS: Overall, ABT-100 has an acceptable pharmacokinetic profile, is well tolerated, and possesses broad-spectrum antitumor activity against a series of xenograft models similar to farnesyltransferase inhibitors in clinical development; therefore, it is an attractive candidate for clinical evaluation.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Imidazoles/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Administración Oral , Inhibidores de la Angiogénesis/farmacocinética , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Área Bajo la Curva , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Humanos , Imidazoles/sangre , Imidazoles/farmacocinética , Interleucina-8/metabolismo , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neovascularización Patológica/prevención & control , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Two novel series of potent and selective FTase inhibitors have been synthesized using structure-based design. Medicinal chemistry efforts led to the discovery of compound 4e with potent cellular activity and good oral bioavailability in dog. A synthetic route toward novel heterocycles 1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2-carbonitrile was established. The structure of compound 5c was confirmed by X-ray crystallography.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Piridinas/síntesis química , Administración Oral , Transferasas Alquil y Aril/química , Animales , Cristalografía por Rayos X , Perros , Farnesiltransferasa , Piridinas/química , Relación Estructura-ActividadRESUMEN
Selective induction of vascular damage within a growing tumor is a potentially important approach in the search for potent anticancer therapeutics. Tubulin-binding (antimitotic) agents destabilize cellular microtubules, suppress tumor growth, and exert antivascular effects with varying degrees of tumor selectivity in preclinical models. The tumor-selective, antivascular effects of ABT-751, a novel, orally active antimitotic agent, currently in phase II clinical development, were characterized in vivo in the present study. We developed an in vivo rat model designed to quantify acute changes in regional vascular resistance (VR) in both tumor and non-tumor vascular beds simultaneously. Tissue-isolated tumors (1 g) with blood flow supplied by a single epigastric artery were grown in rats. Subsequently, tumor blood flow was measured under anesthesia in solid tumors and also in mesenteric, renal, and normal epigastric arteries. Phenylephrine-induced (1 micromol/kg) increases in VR were not different between tumor and non-tumor epigastric arteries, suggesting that tumor vessels possess relatively normal vasoconstrictive function. ABT-751 (3, 10, and 30 mg/kg; i.v.) produced modest transient increases in mean arterial pressure with no effect on heart rate. Tumor VR increased to 75+/-36, 732+/-172, and 727+/-125% above baseline, respectively (P<0.05 for the 10 and 30 mg/kg doses), whereas VR in normal epigastric arteries was not significantly affected. Administration of ABT-751 produced transient modest ( P<0.05) increases in mesenteric VR and no effect on renal VR. These results demonstrate that ABT-751 produces marked reductions in tumor blood flow in the intact rat at doses that exert negligible effects on normal vascular function.
Asunto(s)
Neoplasias Abdominales/irrigación sanguínea , Antineoplásicos/farmacología , Glioma/irrigación sanguínea , Sulfonamidas/farmacología , Resistencia Vascular/efectos de los fármacos , Neoplasias Abdominales/veterinaria , Administración Oral , Animales , Modelos Animales de Enfermedad , Glioma/veterinaria , Hemodinámica/efectos de los fármacos , Masculino , Neoplasias Experimentales/irrigación sanguínea , Piridonas , Ratas , Ratas Endogámicas F344 , Tubulina (Proteína)/metabolismoRESUMEN
A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to explain the improved selectivity for this new series of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent cellular activity (EC(50) = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t(1/2), and 0.19 L/(h x kg) plasma clearance).
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Transferasas Alquil y Aril/antagonistas & inhibidores , Benzamidas/síntesis química , Imidazoles/síntesis química , Nitrilos/síntesis química , Administración Oral , Transferasas Alquil y Aril/química , Transferasas Alquil y Aril/metabolismo , Animales , Benzamidas/farmacocinética , Benzamidas/farmacología , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Farnesiltransferasa , Imidazoles/farmacocinética , Imidazoles/farmacología , Modelos Moleculares , Estructura Molecular , Nitrilos/farmacocinética , Nitrilos/farmacología , Relación Estructura-ActividadRESUMEN
Farnesyltransferase inhibitors (FTIs) have been developed as potential anti-cancer agents due to their efficacy in blocking malignant growth in a variety of murine models of human tumors. To that end, we have developed a series of pyridone farnesyltransferase inhibitors with potent in vitro and cellular activity. The synthesis, SAR and biological properties of these compounds will be discussed.