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首页> 外文期刊>British Journal of Cancer >A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity
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A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity

机译：AKT抑制剂的系统分子和药理学评估揭示了对其生物活性的新洞察力

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Background AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants. Methods We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity. Results Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations. Conclusions These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options.
机译：背景AKT是磷酸阳性3-激酶（PI3K）信号级联的临界效应器，是一种在肿瘤学中的持续治疗靶标。两种不同的AKT抑制剂一直在临床开发，ATP竞争和变构。药物活动的类特异性差异很可能是治疗有效目标结合的差异结构和构象要求的结果，这最终决定了对临床相关的AKT突变体变体的同种型特异性效力，选择性谱和活性。方法对临床AKT抑制剂进行了系统评价，使用体外药理学，分子分析和生物化学测定与结构建模，以更好地理解药物特异性和药物类特异性细胞杀灭活性的背景。结果我们的数据在ATP竞争性和颠覆性AKT抑制剂之间表现出明显的差异，包括通过新功能读数测量的非催化活性的差异效应。令人惊讶的是，我们发现，尽管AKT同种型具有高结构保护，但是一些突变可能以同种类选择性的方式导致耐药性。最后，我们衍生出毒品类特异性磷蛋白蛋白质签名，并用它们来识别有效的药物组合。结论这些研究结果说明了单个AKT抑制剂的效用，无论是药物还是作为化学探针，以及AKT抑制剂药理多样性的益处在提供了特异性特异性治疗选择的曲目方面。

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