RESUMO
PURPOSE: The phosphoinositide 3-kinase (PI3K) pathway is a major oncogenic signaling pathway and an attractive target for therapeutic intervention. Signaling through the PI3K pathway is moderated by the tumor suppressor PTEN, which is deficient or mutated in many human cancers. Molecular characterization of the PI3K signaling network has not been well defined in lung cancer; in particular, the role of PI3Kß and its relation to PTEN in non-small cell lung cancer NSCLC remain unclear. EXPERIMENTAL DESIGN: Antibodies directed against PI3Kß and PTEN were validated and used to examine, by immunohistochemistry, expression in 240 NSCLC resection tissues [tissue microarray (TMA) set 1]. Preliminary observations were extended to an independent set of tissues (TMA set 2) comprising 820 NSCLC patient samples analyzed in a separate laboratory applying the same validated antibodies and staining protocols. The staining intensities for PI3Kß and PTEN were explored and colocalization of these markers in individual tumor cores were correlated. RESULTS: PI3Kß expression was elevated significantly in squamous cell carcinomas (SCC) compared with adenocarcinomas. In contrast, PTEN loss was greater in SCC than in adenocarcinoma. Detailed correlative analyses of individual patient samples revealed a significantly greater proportion of SCC in TMA set 1 with higher PI3Kß and lower PTEN expression when compared with adenocarcinoma. These findings were reinforced following independent analyses of TMA set 2. CONCLUSIONS: We identify for the first time a subset of NSCLC more prevalent in SCC, with elevated expression of PI3Kß accompanied by a reduction/loss of PTEN, for whom selective PI3Kß inhibitors may be predicted to achieve greater clinical benefit.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , PTEN Fosfo-Hidrolase/biossíntese , Fosfatidilinositol 3-Quinases/biossíntese , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Análise Serial de TecidosRESUMO
The structure-activity relationship of a novel subseries of 4-anilinoquinazoline EGFR inhibitors substituted at the C-6 position with carbon-linked side chains has been investigated. This exploration has led to the discovery of novel aminomethyl carboxamides with good biological, pharmacokinetic and physical properties.
Assuntos
Receptores ErbB/antagonistas & inibidores , Quinazolinas/química , Quinazolinas/farmacologia , Administração Oral , Animais , Cães , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Using a high-throughput screening campaign, we identified the 4,6-bis anilino pyrimidines as inhibitors of the cyclin-dependent kinase, CDK4. Herein we describe the further chemical modification and use of X-ray crystallography to develop potent and selective in vitro inhibitors of CDK4.
Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas Proto-Oncogênicas , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Sítios de Ligação , Cristalografia por Raios X , Quinase 4 Dependente de Ciclina , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirimidinas/síntese química , Relação Estrutura-AtividadeRESUMO
Through chemical modification and X-ray crystallography we identified the 2,4-bis anilino pyrimidines as potent inhibitors of CDK4. Herein, we describe the optimisation of this series.
Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas Proto-Oncogênicas , Pirimidinas/farmacologia , Trifosfato de Adenosina/química , Animais , Antineoplásicos/síntese química , Sítios de Ligação , Cristalografia por Raios X , Quinase 4 Dependente de Ciclina , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirimidinas/síntese química , Relação Estrutura-AtividadeRESUMO
High-throughput screening identified the imidazo[1,2-a]pyridine and bisanilinopyrimidine series as inhibitors of the cyclin-dependent kinase CDK4. Comparison of their experimentally-determined binding modes and emerging structure-activity trends led to the development of potent and selective imidazo[1,2-a]pyridine inhibitors for CDK4 and in particular CDK2.