Lysine-targeting irreversible covalent inhibitors have attracted growing interests in recent years, especially in the fields of kinase research. Despite encouraging progress, few chemistries are available to develop inhibitors that are exclusively lysine-targeting, selective, and cell-active. We report herein a 2-ethynylbenzaldehyde (EBA)-based, lysine-targeting strategy to generate potent and selective small-molecule inhibitors of ABL kinase by selectively targeting the conserved catalytic lysine in the enzyme. We showed the resulting compounds were cell-active, capable of covalently engaging endogenous ABL kinase in K562 cells with long-residence time and few off-targets. We further validated the generality of this strategy by developing EBA-based irreversible inhibitors against EGFR (a kinase) and Mcl-1 (a nonkinase) that covalently reacted with the catalytic and noncatalytic lysine within each target.

中文翻译：

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基于 2-乙炔基苯甲醛的赖氨酸靶向蛋白激酶和非激酶的不可逆共价抑制剂

近年来，赖氨酸靶向不可逆共价抑制剂引起了越来越多的兴趣，尤其是在激酶研究领域。尽管取得了令人鼓舞的进展，但很少有化学物质可用于开发专门针对赖氨酸、具有选择性和细胞活性的抑制剂。我们在此报告了一种基于 2-乙炔基苯甲醛 (EBA) 的赖氨酸靶向策略，通过选择性地靶向酶中保守的催化赖氨酸来生成有效且选择性的 ABL 激酶小分子抑制剂。我们表明所得化合物具有细胞活性，能够共价结合 K562 细胞中的内源性 ABL 激酶，且停留时间长且脱靶率低。