顺铂
化学
药品
癌细胞
药理学
DNA聚合酶
IC50型
药物发现
癌症
抗药性
酶
生物化学
化疗
体外
生物
遗传学
作者
Federico Munafò,Michela Nigro,Nicoletta Brindani,Jacopo Manigrasso,Inacrist Geronimo,Giuliana Ottonello,Andrea Armirotti,Marco De Vivo
标识
DOI:10.1016/j.ejmech.2022.115044
摘要
In cancer cells, Pol η allows DNA replication and cell proliferation even in the presence of chemotherapeutic drug-induced damages, like in the case of platinum-containing drugs. Inhibition of Pol η thus represents a promising strategy to overcome drug resistance and preserve the effectiveness of chemotherapeutic drugs. Here, we report the discovery of a novel class of Pol ƞ inhibitors, with 35 active close analogs. Compound 21 (ARN24964) stands out as the best inhibitor, with an IC50 value of 14.7 μM against Pol η and a good antiproliferative activity when used in combination with cisplatin - with a synergistic effect in three different cancer cell lines (A375, A549, OVCAR3). Moreover, it is characterized by a favorable drug-like profile in terms of its aqueous kinetic solubility, plasma and metabolic stability. Thus, ARN24964 is a promising compound for further structure-based drug design efforts toward developing drugs to solve or limit the issue of drug resistance to platinum-containing drugs in cancer patients.
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