RESUMEN
HER2 kinase as a well-established target for breast cancer (BC) therapy is associated with aggressive clinical outcomes; thus, herein we present structural optimization for HER2-selective targeting. HER2 profiling of the developed derivatives demonstrated potent and selective inhibitions (IC50: 5.4-12 nM) compared to lapatinib (IC50: 95.5 nM). Favorably, 17d exhibited minimum off-target kinase activation. NCI-5-dose screening revealed broad-spectrum activities (GI50: 1.43-2.09 µM) and 17d had a remarkable selectivity toward BC. Our compounds revealed significant selective and potent antiproliferative activities (â¼20-fold) against HER2+ (AU565, BT474) compared to HER2(-) cells. At 0.1 IC50, 15i, 17d, and 25b inhibited pERK1/2 and pAkt by immunoblotting. Furthermore, 17d demonstrated potent in vivo tumor regression against the BT474 xenograft model. Notably, a metastasis case was observed in the vehicle but not in the test mice groups. CD-1 mice metabolic stability assay revealed high stability and low intrinsic clearance of 17d (T1/2 > 145 min and CLint(mic) < 9.6 mL/min/kg).
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Diseño de Fármacos , Lapatinib/química , Terapia Molecular Dirigida , Quinazolinas/síntesis química , Quinazolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidores , Animales , Apoptosis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas In Vitro , Ratones , Ratones Desnudos , Receptor ErbB-2/metabolismo , Transducción de Señal , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Four series of some 4-substituted-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives 5a-f, 6a-f, 8a-f, and 9a-f were designed to be screened for their antitumor activity. All compounds were evaluated against breast (MCF-7) and lung (A-549) cell lines. Six compounds 5a, 5b, 6b, 6e, 9e, and 9f displaying activity against both cell lines were further estimated for their EGFR-TK inhibitory activity where they revealed 41-91% inhibition and compound 6b elicited the highest activity (91%). A docking study of these compounds into the ATP-binding site of EGFR-TK demonstrated their binding mode where H-bonding interaction with Met793 through N(1) of pyrimidine or N(2) of pyrazole was observed.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Antineoplásicos/química , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Receptores ErbB/metabolismo , Humanos , Enlace de Hidrógeno , Células MCF-7 , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/química , Estructura Terciaria de Proteína , Pirazoles/síntesis química , Pirimidinas/síntesis química , Relación Estructura-ActividadRESUMEN
Several analogues of the general formulae 2-methoxy-9-substituted acridine and 6-chloro-2-methoxy-9-substituted acridine were synthesized and evaluated in vitro at 6.25 microg/mL against M. tuberculosis H37Rv. Compounds 15 and 17 showed potential antitubercular activity with 100% inhibition to the virulent mycobacterium.