RESUMEN
The mutant receptor tyrosine kinase EGFR is a validated and therapeutically amenable target for genotypically selected lung cancer patients. Here we present the synthesis and biological evaluation of a series of 6- and 7-substituted 4-anilinoquinolines as potent type I inhibitors of clinically relevant mutant variants of EGFR. Quinolines 3a and 3e were found to be highly active kinase inhibitors in biochemical assays and were further investigated for their biological effect on EGFR-dependent Ba/F3 cells and non-small cell lung cancer (NSCLC) cell lines.
Asunto(s)
Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Receptores ErbB/química , Receptores ErbB/genética , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Mutación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Relación Estructura-ActividadRESUMEN
Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival of patients with EGFR-mutated lung cancers. Second-generation EGFR inhibitors introduced to overcome acquired resistance by the T790M resistance mutation of EGFR have thus far shown limited clinical activity in patients with T790M-mutant tumors. In this study, we systematically analyzed the determinants of the activity and selectivity of the second-generation EGFR inhibitors. A focused library of irreversible as well as structurally corresponding reversible EGFR-inhibitors was synthesized for chemogenomic profiling involving over 79 genetically defined NSCLC and 19 EGFR-dependent cell lines. Overall, our results show that the growth-inhibitory potency of all irreversible inhibitors against the EGFR(T790M) resistance mutation was limited by reduced target inhibition, linked to decreased binding velocity to the mutant kinase. Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis. Our findings offer a mechanistic explanation for the limited efficacy of irreversible EGFR inhibitors in EGFR(T790M) gatekeeper-mutant tumors, and they prompt combination treatment strategies involving inhibitors that target signaling downstream of the EGFR.
Asunto(s)
Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Afatinib , Sustitución de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Análisis por Conglomerados , Receptores ErbB/metabolismo , Furanos/farmacología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/clasificación , Piridinas/farmacología , Pirimidinas/farmacología , Quinazolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Synthesis of highly functionalized 2(1H)-pyrazinone 3-carboxamide derivatives is reported. A one-pot, two-step process including the base-mediated reaction of N,N-disubstituted aminoacetonitrile derivatives 18 with 3,5-dihalo-2(1H)-pyrazinones 1 afforded substituted aminoacetonitrile pyrazinone derivative 19, which on subsequent oxidation followed by transamidation of the resulting intermediate with primary or secondary amines gave the corresponding highly functionalized 2(1H)-pyrazinone 3-carboxamide derivatives 21.
