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1.
Int J Cancer ; 126(5): 1226-34, 2010 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-19676042

RESUMEN

17-AAG, the first-generation clinical Hsp90 inhibitor, exhibits promising antitumor activity in clinical studies, but is limited by poor solubility and hepatotoxicity. To pursue compounds with better biopharmaceutical properties, we have developed a series of fully synthetic orally bioavailable inhibitors of Hsp90. Here, we report that 17-AAG and other ansamycin derivatives are inactive in P-gp and/or MRP-1 expressing cell lines and sensitivity could be restored by coadministration of P-gp or MRP inhibitors. In contrast, the synthetic Hsp90 inhibitor, BIIB021 was active in these models. Accordingly, BIIB021 was considerably more active than 17-AAG against adrenocortical carcinoma, a tumor that naturally expresses P-gp, both in vitro and in vivo. This efflux pump-mediated resistance is manifested in both cytotoxicity assays and measurements of target inhibition, such as client protein degradation. Other than this, the cytotoxic activity of BIIB021 was also not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. Our results indicate that the activity of 17-AAG and other ansamycins may be curtailed in tumors that have upregulated efflux pumps or antiapoptotic proteins or other genetic alterations. These data indicate that the new generation of synthetic anti-Hsp90 drugs, exemplified by BIIB021 that is currently undergoing Phase II testing, may have broader application against tumors with acquired multidrug resistance or tumors located in organs protected by MDR proteins, such as the adrenal glands, brain and testis.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adenina/análogos & derivados , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Piridinas/farmacología , Adenina/farmacología , Animales , Benzoquinonas/farmacología , Western Blotting , Línea Celular Tumoral , Femenino , Citometría de Flujo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Humanos , Lactamas Macrocíclicas/farmacología , Ratones , Ratones Desnudos , Neoplasias Experimentales/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Mol Cancer Ther ; 8(4): 921-9, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19372565

RESUMEN

Inhibition of heat shock protein 90 (Hsp90) results in the degradation of oncoproteins that drive malignant progression, inducing cell death, making Hsp90 a target of substantial interest for cancer therapy. BIIB021 is a novel, fully synthetic inhibitor of Hsp90 that binds competitively with geldanamycin in the ATP-binding pocket of Hsp90. In tumor cells, BIIB021 induced the degradation of Hsp90 client proteins including HER-2, AKT, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27. BIIB021 treatment resulted in growth inhibition and cell death in cell lines from a variety of tumor types at nanomolar concentrations. Oral administration of BIIB021 led to the degradation of Hsp90 client proteins measured in tumor tissue and resulted in the inhibition of tumor growth in several human tumor xenograft models. Studies to investigate the antitumor effects of BIIB021 showed activity on both daily and intermittent dosing schedules, providing dose schedule flexibility for clinical studies. Assays measuring the HER-2 protein in tumor tissue and the HER-2 extracellular domain in plasma were used to show interdiction of the Hsp90 pathway and utility as potential biomarkers in clinical trials for BIIB021. Together, these data show that BIIB021 is a promising new oral inhibitor of Hsp90 with antitumor activity in preclinical models.


Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/farmacología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Neoplasias Experimentales/tratamiento farmacológico , Piridinas/farmacología , Adenina/administración & dosificación , Adenina/farmacocinética , Adenina/farmacología , Administración Oral , Animales , Benzoquinonas/farmacología , Western Blotting , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Lactamas Macrocíclicas/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo , Piridinas/administración & dosificación , Piridinas/farmacocinética , Receptor ErbB-2/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Int J Cancer ; 120(4): 918-26, 2007 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-17131314

RESUMEN

The geldanamycin derivative 17-allyamino-17-demethoxygeldanamycin (17-AAG) is a clinical stage ATP-competitive HSP90 inhibitor that induces degradation of HSP90 client proteins. 17-AAG contains 1 ansamycin moiety and is highly potent in conventional cell killing assays. Since active Hsp90 exists as a dimer, we hypothesized that dimeric compounds containing 2 ansamycin pharmacophores might inhibit Hsp90 function more efficiently than 17-AAG. Here, we show that monomeric and dimeric ansamycins exert their activity in distinct ways. Under conditions of continuous exposure, 17-AAG induced client degradation and cell growth inhibition more readily than the dimeric drugs CF237 and CF483. By contrast, 24 hr treatment of various tumor cells with 17-AAG followed by drug washout caused temporary client degradation and cell cycle arrest but minimal cell death, whereas both dimers induced massive apoptosis. CF237 remained bound to Hsp90 for days after drug withdrawal and, while both monomeric and dimeric compounds caused accumulation of the inactive intermediate Hsp90 complex, this effect disappeared following washout of 17-AAG but not CF237. The dimer was also retained for longer in tumor xenografts and displayed superior antitumor activity in vivo. These results indicate that monomeric and dimeric Hsp90 inhibitors have distinct biological profiles and work differentially toward target inhibition.


Asunto(s)
Antineoplásicos/uso terapéutico , Benzoquinonas/uso terapéutico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Lactamas Macrocíclicas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Western Blotting , Proliferación Celular/efectos de los fármacos , Dimerización , Citometría de Flujo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Rifabutina/análogos & derivados , Rifabutina/farmacología , Células Tumorales Cultivadas/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Mol Cancer Ther ; 5(5): 1256-64, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16731758

RESUMEN

The selective heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) is currently in phase I/II clinical studies at numerous institutions. Heretofore, the biomarkers to detect 17-AAG bioactivity (Hsp70, Raf-1, and cyclin-dependent kinase 4) had to be analyzed by Western blot of cellular samples, either from tumor biopsies or peripheral blood leukocytes, a method that is both laborious and invasive. We have identified two new biomarkers [insulin-like growth factor binding protein-2 (IGFBP2) and HER-2 extracellular domain] that can be readily detected in patient sera by ELISA. Both secreted proteins are derived from or regulated by Hsp90 client proteins, raising hopes that they might be sensitive serum markers of HSP90 inhibitor activity. Several structurally unrelated HSP90 inhibitors dose-dependently decreased secretion of both IGFBP-2 and HER-2 extracellular domain into culture medium, and both proteins were more sensitive to HSP90 inhibitors than previously identified biomarkers. In sera from BT474 tumor-bearing mice, both IGFBP-2 and HER-2 extracellular domain were down-regulated by 17-AAG in a time-dependent and dose-dependent manner, coincident with the degradation of HER-2 and attenuation of AKT activity in the tumors. Furthermore, IGFBP-2 levels at the end of treatment correlated with residual tumor load, suggesting that IGFBP-2 might serve as an early indicator of therapeutic response. In addition, we also found that both IGFBP-2 and HER-2 extracellular domain levels are elevated in patient sera from several cancer types, suggesting that these novel secreted biomarkers could be valuable pharmacodynamic tools in clinical trials of HSP90 inhibitors.


Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor/metabolismo , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Receptor ErbB-2/metabolismo , Rifabutina/análogos & derivados , Animales , Benzoquinonas , Biomarcadores de Tumor/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Ensayos Clínicos Fase I como Asunto , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Femenino , Proteínas HSP90 de Choque Térmico/metabolismo , Técnicas In Vitro , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Lactamas Macrocíclicas , Ratones , Ratones Desnudos , Estructura Terciaria de Proteína/efectos de los fármacos , Receptor ErbB-2/sangre , Receptor ErbB-2/genética , Rifabutina/farmacología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
5.
J Med Chem ; 49(2): 817-28, 2006 Jan 26.
Artículo en Inglés | MEDLINE | ID: mdl-16420067

RESUMEN

Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such as 4 were disclosed as Hsp90 inhibitors, but these compounds are not water soluble and consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results in compounds that are potent, soluble in aqueous media, and orally bioavailable. In an HER-2 degradation assay, the highest potency was achieved with the neopentylamine 42 (HER-2 IC(50) = 90 nM). In a murine tumor xenograft model (using the gastric cancer cell line N87), the H(3)PO(4) salts of the amines 38, 39, and 42 induced tumor growth inhibition when administered orally at 200 mg/kg/day. The amines 38, 39, and 42 are the first Hsp90 inhibitors shown to inhibit tumor growth upon oral dosage.


Asunto(s)
Adenina/análogos & derivados , Antineoplásicos/síntesis química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Purinas/síntesis química , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Disponibilidad Biológica , Femenino , Ratones , Ratones Desnudos , Purinas/química , Purinas/farmacología , Solubilidad , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
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