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1.
Blood ; 112(4): 981-9, 2008 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-18495956

RESUMEN

MGCD0103 is an isotype-selective inhibitor of histone deacetylases (HDACs) targeted to isoforms 1, 2, 3, and 11. In a phase 1 study in patients with leukemia or myelodysplastic syndromes (MDS), MGCD0103 was administered orally 3 times weekly without interruption. Twenty-nine patients with a median age of 62 years (range, 32-84 years) were enrolled at planned dose levels (20, 40, and 80 mg/m(2)). The majority of patients (76%) had acute myelogenous leukemia (AML). In all, 24 (83%) of 29 patients had received 1 or more prior chemotherapies (range, 0-5), and 18 (62%) of 29 patients had abnormal cytogenetics. The maximum tolerated dose was determined to be 60 mg/m(2), with dose-limiting toxicities (DLTs) of fatigue, nausea, vomiting, and diarrhea observed at higher doses. Three patients achieved a complete bone marrow response (blasts

Asunto(s)
Benzamidas/administración & dosificación , Benzamidas/farmacocinética , Inhibidores de Histona Desacetilasas , Leucemia/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas/toxicidad , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Leucemia/complicaciones , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Farmacocinética , Pirimidinas/toxicidad
2.
Bioorg Med Chem Lett ; 19(3): 644-9, 2009 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-19114304

RESUMEN

Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.


Asunto(s)
Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Pirimidinas/farmacología , Animales , Antineoplásicos/farmacología , Benzamidas/síntesis química , Línea Celular Tumoral , Proliferación Celular , Química Farmacéutica/métodos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores de Histona Desacetilasas , Humanos , Concentración 50 Inhibidora , Ratones , Trasplante de Neoplasias , Pirimidinas/síntesis química , Relación Estructura-Actividad
3.
Clin Cancer Res ; 14(11): 3441-9, 2008 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-18519775

RESUMEN

PURPOSE: The pharmacodynamic properties of MGCD0103, an isotype-selective inhibitor of histone deacetylase (HDAC), were evaluated in preclinical models and patients with a novel whole-cell HDAC enzyme assay. EXPERIMENTAL DESIGN: Boc-Lys(epsilon-Ac)-AMC, a HDAC substrate with fluorescent readout, was found to be cell permeable and was used to monitor MGCD0103-mediated HDAC inhibition in cultured cancer cells in vitro, in peripheral WBC ex vivo, in mice in vivo, and in human patients. RESULTS: MGCD0103 inhibited HDAC activity in several human cancer cell lines in vitro and in human peripheral WBC ex vivo in a dose-dependent manner. Unlike suberoylanilide hydroxamic acid, the HDAC inhibitory activity of MGCD0103 was time dependent and sustained for at least 24 hours following drug removal in peripheral WBC ex vivo. Inhibitory activity of MGCD0103 was sustained for at least 8 hours in vivo in mice and 48 hours in patients with solid tumors. HDAC inhibitory activity of MGCD0103 in peripheral WBC correlated with induction of histone acetylation in blood and in implanted tumors in mice. In cancer patients, sustained pharmacodynamic effect of MGCD0103 was visualized only by dose-dependent enzyme inhibition in peripheral WBC but not by histone acetylation analysis. CONCLUSIONS: This study shows that MGCD0103 has sustained pharmacodynamic effects that can be monitored both in vitro and in vivo with a cell-based HDAC enzyme assay.


Asunto(s)
Antineoplásicos/administración & dosificación , Benzamidas/administración & dosificación , Bioensayo/métodos , Histona Desacetilasas/análisis , Neoplasias/tratamiento farmacológico , Pirimidinas/administración & dosificación , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Línea Celular Tumoral , Esquema de Medicación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Pirimidinas/efectos adversos , Pirimidinas/farmacocinética , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Mol Cancer Ther ; 7(4): 759-68, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18413790

RESUMEN

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.


Asunto(s)
Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Neoplasias Pulmonares/tratamiento farmacológico , Pirimidinas/farmacología , Acetilación , Animales , Benzamidas/farmacocinética , Inhibidores Enzimáticos/farmacocinética , Femenino , Histona Desacetilasa 1 , Histona Desacetilasa 2 , Histona Desacetilasas/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Técnicas In Vitro , Isoenzimas , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Pirimidinas/farmacocinética , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Células Tumorales Cultivadas , Vorinostat , Ensayos Antitumor por Modelo de Xenoinjerto
5.
Bioorg Med Chem Lett ; 18(4): 1502-6, 2008 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-18207391

RESUMEN

The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.


Asunto(s)
Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Compuestos de Anilina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/química , Mama/citología , Mama/efectos de los fármacos , Línea Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Inhibidores Enzimáticos/química , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células HCT116 , Histona Desacetilasa 1 , Humanos , Imidazoles/síntesis química , Imidazoles/química , Imidazoles/farmacología , Relación Estructura-Actividad
6.
Bioorg Med Chem Lett ; 18(3): 1067-71, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18160287

RESUMEN

Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Pirimidinas/farmacología , Triazinas/síntesis química , Triazinas/farmacología , Animales , Antineoplásicos/química , Benzamidas/química , Modelos Animales de Enfermedad , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Ratones , Relación Estructura-Actividad , Triazinas/química
7.
Cancer Res ; 62(15): 4325-30, 2002 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-12154036

RESUMEN

Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. We have designed and synthesized novel nonhydroxamate sulfonamide anilides that can inhibit human HDAC enzymes and can induce hyperacetylation of histones in human cancer cells. These compounds selectively inhibit proliferation and cause cell cycle blocks in various human cancer cells but not in normal cells. The growth inhibitory activity of sulfonamide anilides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. One of these compounds (Compound 2) can significantly reduce tumor growth of implanted human colon tumors in nude mice. Unlike another anilide-based HDAC inhibitor, MS-275, which decreases both red and white blood counts and reduces spleen weights in mice, Compound 2 does not exhibit noticeable toxicity. By using cDNA array analysis, we have identified downstream genes whose expression is altered by Compound 2 in human cancer cells. In correlation with its antitumor activity both in vitro and in vivo, Compound 2 induces expression of p21(WAF1/Cip1), gelsolin, and keratin 19, while down-regulating expression of cyclin A and cyclin B1 in human cancer cells in a dose-dependent manner. Our results suggest that sulfonamide anilides are novel HDAC inhibitors and may be useful as antiproliferative agents in cancer chemotherapy.


Asunto(s)
Anilidas/farmacología , Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas , Sulfonamidas/farmacología , Acetilación/efectos de los fármacos , Anilidas/toxicidad , Animales , Antineoplásicos/toxicidad , Benzamidas/farmacología , Benzamidas/toxicidad , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Ciclina A/biosíntesis , Ciclina B/biosíntesis , Ciclina B1 , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/biosíntesis , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/toxicidad , Femenino , Fase G2/efectos de los fármacos , Histonas/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitosis/efectos de los fármacos , Piridinas/farmacología , Piridinas/toxicidad , Sulfonamidas/toxicidad , Ensayos Antitumor por Modelo de Xenoinjerto
8.
J Med Chem ; 46(5): 820-30, 2003 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-12593661

RESUMEN

A series of sulfonamide hydroxamic acids and anilides have been synthesized and studied as histone deacetylase (HDAC) inhibitors that can induce hyperacetylation of histones in human cancer cells. The inhibition of HDAC activity represents a novel approach for intervening in cell cycle regulation. The lead candidates were screened in a panel of human tumor and normal cell lines. They selectively inhibit proliferation, cause cell cycle blocks, and induce apoptosis in human cancer cells but not in normal cells. The structure-activity relationships, the antiproliferative activity, and the in vivo efficacy are described.


Asunto(s)
Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/síntesis química , Sulfonamidas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Trasplante Heterólogo
9.
J Clin Oncol ; 26(12): 1940-7, 2008 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-18421048

RESUMEN

PURPOSE: MGCD0103 is a novel isotype-selective inhibitor of human histone deaceylases (HDACs) with the potential to regulate aberrant gene expression and restore normal growth control in malignancies. PATIENTS AND METHODS: A phase I trial of MGCD0103, given as a three-times-per-week oral dose for 2 of every 3 weeks, was performed in patients with advanced solid tumors. Primary end points were safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity, and histone acetylation status in peripheral WBCs. RESULTS: Six dose levels ranging from 12.5 to 56 mg/m(2)/d were evaluated in 38 patients over 99 cycles (median, 2; range, 1 to 11). The recommended phase II dose was 45 mg/m(2)/d. Dose-limiting toxicities consisting of fatigue, nausea, vomiting, anorexia, and dehydration were observed in three (27%) of 11 and two (67%) of three patients treated at the 45 and 56 mg/m(2)/d dose levels, respectively. Disease stabilization for four or more cycles was observed in five (16%) of 32 patients assessable for efficacy. PK analyses demonstrated interpatient variability which was improved by coadministration with low pH beverages. Elimination half-life ranged from 6.7 to 12.2 hours, and no accumulation was observed with repeated dosing. PD evaluations confirmed inhibition of HDAC activity and induction of acetylation of H3 histones in peripheral WBCs from patients by MGCD0103. CONCLUSION: At doses evaluated, MGCD0103 appears tolerable and exhibits favorable PK and PD profiles with evidence of target inhibition in surrogate tissues.


Asunto(s)
Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Neoplasias/tratamiento farmacológico , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Acetilación/efectos de los fármacos , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Benzamidas/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Inhibidores de Histona Desacetilasas , Histonas/sangre , Humanos , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/enzimología , Neoplasias/metabolismo , Cooperación del Paciente , Pirimidinas/farmacocinética
10.
J Med Chem ; 51(14): 4072-5, 2008 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-18570366

RESUMEN

The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.


Asunto(s)
Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Pirimidinas/farmacología , Administración Oral , Animales , Benzamidas/administración & dosificación , Benzamidas/química , Perros , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad
11.
Bioorg Med Chem Lett ; 16(15): 4048-52, 2006 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-16713259

RESUMEN

Inhibition of histone deacetylases (HDACs) is emerging as a new strategy in human cancer therapy. Novel 2-aminophenyl benzamides and acrylamides, that can inhibit human HDAC enzymes and induce hyperacetylation of histones in human cancer cells, have been designed and synthesized. These compounds selectively inhibit proliferation and cause cell cycle arrest in various human cancer cells but not in normal cells. The growth inhibition of 2-aminophenyl benzamides and acrylamides against human cancer cells in vitro is reversible and is dependent on the induction of histone acetylation. Compounds of this class can significantly reduce tumor growth in human tumor xenograft models.


Asunto(s)
Acrilamidas/farmacología , Benzamidas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Acrilamidas/química , Benzamidas/química , Línea Celular Tumoral , Inhibidores Enzimáticos/química , Humanos , Relación Estructura-Actividad
12.
Bioorg Med Chem Lett ; 14(1): 283-7, 2004 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-14684344

RESUMEN

A variety of omega-substituted alkanoic acid (2-amino-phenyl)-amides were designed and synthesized. These compounds were shown to inhibit recombinant human histone deacetylases (HDACs) with IC(50) values in the low micromolar range and induce hyperacetylation of histones in whole cells. They induced expression of p21WAF1/Cip1 and caused cell-cycle arrest in human cancer cells. Compounds in this class showed efficacy in human tumor xenograft models.


Asunto(s)
Amidas/química , Amidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Ciclo Celular/efectos de los fármacos , Ciclo Celular/fisiología , Línea Celular Tumoral , Histona Desacetilasas/metabolismo , Humanos
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