RESUMO
The enhancer of zeste homologue 2 (EZH2) is the core catalytic subunit of polycomb repressive complex 2, which catalyzes lysine 27 methylation of histone H3. Herein, a series of quinolinone derivatives were designed and synthesized based on the structure of Tazemetostat as the lead compound. Compound 9l (EZH2WT IC50 = 0.94 nM) showed stronger antiproliferative activity in HeLa cells than the lead compound. Moreover, compound 9e (EZH2WT IC50 = 1.01 nM) significantly inhibited the proliferation and induced apoptosis in A549 cells.
Assuntos
Proliferação de Células , Desenho de Fármacos , Proteína Potenciadora do Homólogo 2 de Zeste , Quinolonas , Humanos , Quinolonas/farmacologia , Quinolonas/síntese química , Quinolonas/química , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Células HeLa , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células A549 , Estrutura Molecular , Relação Dose-Resposta a Droga , Linhagem Celular TumoralRESUMO
Calmodulin mutations can cause life-threatening long QT syndrome involving CALM1, CALM2, and CALM3. In this study, human induced pluripotent stem cells ZZUNEUi030-A were derived from a female patient with heterozygous CALM2 gene c. 395A â T by Sendai virus non-integrated reprogramming technology. The cell line showed a normal female karyotype (46, XX), expressed pluripotency markers, and had the ability to differentiate into three germ layers in vitro. ZZUNEUi030-A can be used as a cell disease model to study the pathogenesis of LQT caused by calmodulin mutations.