摘要
背景:碳酸酐酶(CAs)通过二氧化碳的可逆水合作用调节pH稳态,从而成为许多重要功能的必需酶。在人类12种具有催化活性的CA亚型中,CA IX因其在癌症进展中的作用而成为相关的治疗靶点。只有两种CA IX抑制剂进入临床试验,主要是由于低亲和力和选择性特性。 目的:本文综述了纳米-皮摩尔选择性CA IX抑制剂VD11-4-2、VR16-09和VD12-09的设计、开发和鉴定。 方法与结果:化合物从我们的数据库中选择,由400多种苯磺酰胺组成,在我们的实验室合成,并测试了它们与12种人类CAs的结合。在此,我们讨论了CA CO2水合酶活性/抑制试验和一些生物物理技术,如荧光热移试验和等温滴定量热法,突出了它们在化合物亲和和结构活性关系分析方面的贡献。为了获得足够数量的重组CA用于抑制剂筛选,提出了几种基因克隆和蛋白纯化策略,包括定点CA突变体、来自爪蟾卵母细胞的异源CA和内生CA。以癌细胞为基础的方法,如克隆原性、细胞外酸化和质谱气相分析,证实了在完整癌细胞中铅抑制剂的纳摩尔活性。 结论:新型CA IX抑制剂是有前途的体内探索衍生物。此外,在肿瘤酸中毒和转运代谢中断的同时靶向参与质子通量的几种蛋白可能改善癌症管理。
关键词: 药物开发,有机化学,癌症,磺酰胺,热位移测定,等温滴定量热法,CA IX
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