Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ∼200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer a general strategy, as an alternative to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.

中文翻译：

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选择性靶向 PI3Kδ 的激酶组保守赖氨酸作为共价激酶抑制的一般方法

迄今为止，通过靶向保守性较差的半胱氨酸对激酶进行选择性共价抑制已证明在化学探针和批准药物的开发中非常富有成效。然而，这种方法仅限于大约 200 种在 ATP 结合口袋附近具有这种半胱氨酸的激酶。在此，我们报告了一种通过靶向保守的催化赖氨酸残基来实现选择性、不可逆激酶抑制的新方法。我们通过开发选择性的共价 PI3Kδ 抑制剂来说明我们的方法，这些抑制剂在细胞测定中表现出纳摩尔级的效力，并且在 CD4+ T 细胞中的作用持续时间大于 48 小时。尽管赖氨酸残基在整个激酶组中得到保护，但在生化分析中，先导化合物对一系列脂质和蛋白激酶显示出高水平的选择性，以及在活细胞蛋白质组学研究中与极少数脱靶蛋白共价结合。我们预计这种方法可以提供一种通用策略，作为靶向非保守半胱氨酸的替代方案，用于开发选择性共价激酶抑制剂。