Selectivity and therapeutic inhibition of kinases: to be or not to be?
Selectivity and therapeutic inhibition of kinases: to be or not to be?
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蛋白激酶在所有细胞的信号通路中起关键作用，是常用的治疗靶点。目前，美国已经批准了8种激酶抑制剂，每一种都具有纳摩尔效价。虽然最初的目标是产生具有高度选择性的抑制剂，但最近的经验表明，许多这些批准的化合物靶向不止一种激酶。令人惊讶的是，这种滥交并没有人们想象的那么成问题；事实上，它开辟了新的治疗机会。本文将讨论一类新的免疫抑制药物Janus激酶抑制剂的研究现状，以及选择性抑制该类激酶的优缺点。
Protein kinases, which serve critical functions in signaling pathways in all cells, are popular therapeutic targets. At present, eight kinase inhibitors have been approved in the United States, each of which shows nanomolar potency. Although the initial goal was to generate inhibitors with a high degree of selectivity, recent experience has revealed that many of these approved compounds target more than one kinase. Surprisingly, this promiscuity is less problematic than one would have imagined; indeed, it opens new therapeutic opportunities. In this Perspective, we discuss the present status of Janus kinase inhibitors – a new class of immunosuppressive drugs – and the advantages and disadvantages of selectively inhibiting this class of kinase.
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有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
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