RESUMO
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 Assuntos
Benzamidas/administração & dosagem
, Benzamidas/farmacocinética
, Inibidores de Histona Desacetilases
, Leucemia/tratamento farmacológico
, Pirimidinas/administração & dosagem
, Pirimidinas/farmacocinética
, Administração Oral
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Benzamidas/toxicidade
, Células Cultivadas
, Relação Dose-Resposta a Droga
, Feminino
, Histona Desacetilases/metabolismo
, Histonas/metabolismo
, Humanos
, Leucemia/complicações
, Leucemia Mieloide Aguda/complicações
, Leucemia Mieloide Aguda/tratamento farmacológico
, Masculino
, Dose Máxima Tolerável
, Pessoa de Meia-Idade
, Farmacocinética
, Pirimidinas/toxicidade
RESUMO
MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC(50) (concentration lethal to 50%) of 0.23 micromol/l and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of two cycles of MGCD0103 (range, 0-12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22.3) or del(17p13.1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and four patients received concomitant rituximab, with no improvement in response. Grade 3-4 toxicity consisted of infections, thrombocytopenia, anaemia, diarrhoea, and fatigue. HDAC inhibition was observed in six out of nine patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirimidinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Aberrações Cromossômicas , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Histona Desacetilases/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Rituximab , Resultado do TratamentoRESUMO
A series of N-(3-fluoro-4-(2-arylthieno[3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Assuntos
Amidas/química , Imidazolidinas/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/administração & dosagem , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Amidas/farmacologia , Animais , Linhagem Celular Tumoral , Células HCT116 , Humanos , Imidazolidinas/farmacologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Ratos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
A series of N-(4-(6,7-disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting c-Met and VEGFR2 tyrosine kinases was designed and synthesized. The compounds were potent against these two enzymes with IC(50) values in the low nanomolar range in vitro, possessed favorable pharmacokinetic profiles and showed high efficacy in vivo in several human tumor xenograft models in mice.
Assuntos
Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Bioensaio/métodos , Histona Desacetilases/análise , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Linhagem Celular Tumoral , Esquema de Medicação , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Inibidores de Histona Desacetilases , Histona Desacetilases/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases is described. The compounds demonstrated potency with IC(50) values in the low nanomolar range in vitro while the lead compound also showed in vivo activity against various human tumor xenograft models in mice. Further exploration of this class of compounds is underway.