RESUMEN
FGF2-FGFR1 autocrine pathway activation reduces the sensitivity of non-small cell lung cancer (NSCLC) cells to EGFR inhibitors like Gefitinib. Therefore, dual-specific drugs targeting EGFR and FGFR with high selectivity and activity are required. Through structure analysis of excellent EGFR inhibitors and FGFR inhibitors, we designed and synthesized 33 4,6-pyrimidinediamine derivatives as dual EGFR and FGFR inhibitors and selected BZF 2 as a potential EGFR and FGFR inhibitor after initial cell screening. Then, through kinase testing and western blot analysis, BZF 2 was defined as a dual EGFR and FGFR inhibitor with high selectivity 1and activity. Biological evaluation of NSCLC cell lines with the FGF2-FGFR1 autocrine loop indicated that BZF 2 significantly inhibited cell proliferation (IC50 values for H226 and HCC827 GR were 2.11 µM, and 0.93 µM, respectively), cell migration, and induced cell apoptosis and cell cycle arrest. Anti-tumor activity test in vivo showed that BZF 2 obviously shrank tumor size. Therefore, BZF 2 is a highly selective and potent dual EGFR/FGFR compound with promising therapeutic effects against EGFR/FGFR1-positive NSCLC.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Diaminas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Diaminas/síntesis química , Diaminas/química , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Relación Estructura-ActividadRESUMEN
Sustained activation of STAT3 is closely related to the cancer development, but the inhibitors for STAT3 overexpression are still in the clinical research stage. In this study, a series of 2,6-disubstituted purine derivatives were designed and synthesized, and their biological activities, as small molecule inhibitors of STAT3, were assessed. Compound PD26-TL07 exhibited remarkable antiproliferative activity against three cancer cell lines (IC50 values for HCT-116, SW480 and MDA-MB-231 were 1.77⯱â¯0.35, 1.51⯱â¯0.19, and 1.25⯱â¯0.38⯵M, respectively). Moreover, detailed biological assays revealed that PD26-TL07 could effectively inhibited STAT3 phosphorylation, and had little inhibition to others'. The newly discovered PD26-TL07 displayed an expecting anticancer effect both in vitro and in vivo. The molecular docking models revealed that PD26-TL07 could bind to the SH2 domain of STAT3. Three additional compounds (PD26-BZ01, PD26-TL03 and PD26-AS06) were also able to inhibit this phosphorylation. This study described novel 2,6-disubstituted purine derivatives as potent anticancer agents targeting STAT3.
Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Purinas/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Estructura Molecular , Purinas/síntesis química , Purinas/química , Factor de Transcripción STAT3/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
In order to study the anti-inflammatory activity of novel 6-substituted and 6,9-disubstituted purine derivatives, 20 compounds, L1-10 and W1-10, derived from purine and lacking a gold complex were designed, synthesized and their anti-inflammatory activity was screened. LPS-induced TNF-α, IL-1ß, IL-6, PGE2, NO, COX-2 and iNOS mRNA were evaluated, and western blot and NF-κB p65 translocation assay were performed in RAW 264.7 macrophages. Furthermore, carrageenan-induced hind paw edema experiments were performed in mice. Compound L1, L4, W2, and W4 markedly exerted a dose-dependent inhibition of TNF-α, IL-1ß, IL-6 and PGE2 release induced by LPS in RAW 264.7 macrophages. Moreover, these compounds strongly inhibited LPS-induced NO, COX-2 and iNOS mRNA in the same cells. Anti-inflammatory activity tests in vivo showed that L1 and L4 were more effective than Au(L3)(PPh3), a known anti-inflammatory agent, at 2-5â¯h, and W4 was the most effective at 3-5â¯h after dosing. Thus, W2, W4, and L1, L4, could effectively inhibit LPS-induced inflammatory response in vitro and in vivo suggesting a promising role as anti-inflammatory agents.