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2-Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-02-12 , DOI: 10.1021/jacs.2c11595 Peng Chen 1 , Guanghui Tang 2 , Chengjun Zhu 3 , Jie Sun 1 , Xuan Wang 1 , Menghua Xiang 1 , Huisi Huang 3 , Wei Wang 1, 2 , Lin Li 4 , Zhi-Min Zhang 3 , Liqian Gao 1 , Shao Q Yao 2
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-02-12 , DOI: 10.1021/jacs.2c11595 Peng Chen 1 , Guanghui Tang 2 , Chengjun Zhu 3 , Jie Sun 1 , Xuan Wang 1 , Menghua Xiang 1 , Huisi Huang 3 , Wei Wang 1, 2 , Lin Li 4 , Zhi-Min Zhang 3 , Liqian Gao 1 , Shao Q Yao 2
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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：
基于 2-乙炔基苯甲醛、以赖氨酸为靶点的蛋白激酶和非激酶不可逆共价抑制剂
近年来，以赖氨酸为靶点的不可逆共价抑制剂引起了越来越多的兴趣，特别是在激酶研究领域。尽管取得了令人鼓舞的进展，但很少有化学方法可用于开发专门针对赖氨酸的、选择性的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，通过选择性靶向酶中保守的催化赖氨酸来生成 ABL 激酶的有效且选择性的小分子抑制剂。我们证明所得化合物具有细胞活性，能够与 K562 细胞中的内源 ABL 激酶共价结合，且停留时间长且脱靶很少。我们通过开发基于 EBA 的针对 EGFR（一种激酶）和 Mcl-1（一种非激酶）的不可逆抑制剂，进一步验证了该策略的普遍性，这些抑制剂与每个靶点内的催化和非催化赖氨酸发生共价反应。
更新日期：2023-02-12
中文翻译：
基于 2-乙炔基苯甲醛、以赖氨酸为靶点的蛋白激酶和非激酶不可逆共价抑制剂
近年来，以赖氨酸为靶点的不可逆共价抑制剂引起了越来越多的兴趣，特别是在激酶研究领域。尽管取得了令人鼓舞的进展，但很少有化学方法可用于开发专门针对赖氨酸的、选择性的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，通过选择性靶向酶中保守的催化赖氨酸来生成 ABL 激酶的有效且选择性的小分子抑制剂。我们证明所得化合物具有细胞活性，能够与 K562 细胞中的内源 ABL 激酶共价结合，且停留时间长且脱靶很少。我们通过开发基于 EBA 的针对 EGFR（一种激酶）和 Mcl-1（一种非激酶）的不可逆抑制剂，进一步验证了该策略的普遍性，这些抑制剂与每个靶点内的催化和非催化赖氨酸发生共价反应。
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