Elizabeth Anscombe, Elisa Meschini, Regina Mora-Vidal, Mathew P Martin, David Staunton, Matthis Geitmann, U Helena Danielson, Will A Stanley, Lan Z Wang, Tristan Reuillon, Bernard T Golding, Celine Cano, David R Newell, Martin E M Noble, Stephen R Wedge, Jane A Endicott, Roger J Griffin
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引用次数: 0
摘要
改变蛋白激酶 ATP 结合位点内半胱氨酸或赖氨酸残基的不可逆抑制剂通过其独特的作用模式，提供了一种 ATP 竞争性制剂的替代品。4-((6-(环己基甲氧基)-9H-嘌呤-2-基)氨基)苯磺酰胺（NU6102）是一种强效的 CDK2 ATP 竞争性抑制剂，其中的磺酰胺分子靠近一对赖氨酸残基。在 CDK2/NU6102 结构的指导下，我们设计了 6-(环己基甲氧基)-N-(4-(乙烯基磺酰基)苯基)-9H-嘌呤-2-胺（NU6300），如共轭晶体结构所示，它能与 CDK2 共价结合。NU6300 与 SKUT-1B 细胞急性孵育会产生持久的 Rb 磷酸化抑制作用，这与它作为不可逆 CDK2 抑制剂的作用一致。NU6300 是第一个被描述的共价 CDK2 抑制剂，它说明了乙烯基砜在设计更具效力和选择性的化合物方面的潜力。
Identification and Characterization of an Irreversible Inhibitor of CDK2.
Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.
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