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1.
Oncotarget ; 7(3): 2329-42, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26295308

RESUMO

CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4 nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220 nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition.


Assuntos
4-Aminopiridina/análogos & derivados , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quinase 1 do Ponto de Checagem/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , 4-Aminopiridina/farmacocinética , 4-Aminopiridina/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Proteína Quinase CDC2 , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/metabolismo , Quinase do Ponto de Checagem 2/antagonistas & inibidores , Quinases Ciclina-Dependentes/antagonistas & inibidores , Dano ao DNA/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Células HT29 , Humanos , Irinotecano , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos Transgênicos , Pirazinas/farmacocinética , Gencitabina
2.
Clin Cancer Res ; 18(9): 2687-94, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22553374

RESUMO

PURPOSE: This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor. PATIENTS AND METHODS: CHR-3996 was administered orally once a day. This phase I trial used a 3+3 dose-escalation design. PK profiles were analyzed by liquid chromatography-tandem mass spectroscopic methods and PD studies were conducted using ELISA studying histone H3 acetylation in peripheral blood mononuclear cells. RESULTS: Thirty-nine patients were treated at dose levels of 5 mg (n = 3), 10 mg (n = 4), 20 mg (n = 3), 40 mg (n = 10), 80 mg (n = 10), 120 mg (n = 4), and 160 mg (n = 5) administered orally once daily. The dose-limiting toxicities seen were thrombocytopenia (160 mg), fatigue (80 and 120 mg), plasma creatinine elevation (80 and 120 mg), and atrial fibrillation (40 mg). The area under the curve was proportional to the administered dose and a maximal plasma concentration of 259 ng/mL at a dose of 40 mg exceeded the concentrations required for antitumor efficacy in preclinical models. Target inhibition measured by quantification of histone acetylation was shown at doses of 10 mg/d and was maximal at 40 mg. A partial response was seen in one patient with metastatic acinar pancreatic carcinoma. CONCLUSIONS: Taking the toxicity and PK/PD profile into consideration, the recommended phase II dose (RP2D) is 40 mg/d. At this dose, CHR-3996 has a favorable toxicologic, PK, and PD profile. CHR-3996 has shown preliminary clinical activity and should be evaluated in further clinical trials.


Assuntos
Compostos Azabicíclicos/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/química , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Acetilação , Administração Oral , Adulto , Idoso , Compostos Azabicíclicos/farmacocinética , Ensaios Clínicos Fase II como Assunto , Feminino , Seguimentos , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Pirimidinas/farmacocinética , Distribuição Tecidual
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