Cysteine Mapping in Conformationally Distinct Kinase Nucleotide Binding Sites: Application to the Design of Selective Covalent Inhibitors
Cysteine Mapping in Conformationally Distinct Kinase Nucleotide Binding Sites: Application to the Design of Selective Covalent Inhibitors
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DOI：
10.1021/jm101396q
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发表时间：
2011-03-10
影响因子：
7.3
通讯作者：
Winssinger, Nicolas
中科院分区：
文献类型：
--
作者：
Leproult, Emeline;Barluenga, Sofia;Winssinger, Nicolas
激酶已成为最多产的治疗靶点之一。针对激酶核苷酸结合袋的抑制剂治疗成功的一个重要标准是抑制剂的停留时间。最近，共价激酶抑制剂引起了人们的关注，因为它们具有终末抑制作用，因此比具有瞬时抑制作用的可逆抑制剂更有效。设计不可逆抑制剂的最可靠方法是利用靶蛋白中存在的半胱氨酸硫醇基团的亲核性。在此，我们报告了对激酶核苷酸结合位点中存在的半胱氨酸残基的系统分析，考虑到不同的激酶构象，可以利用其进行不可逆抑制。我们通过 KIT/PDGFR 激酶不可逆抑制剂的设计和验证证明了该分析的预测能力。这是共价激酶抑制剂的第一个例子，它将解决 DFG-out 构象的药效团与共价陷阱相结合。
Kinases have emerged as one of the most prolific therapeutic targets. An important criterion in the therapeutic success of inhibitors targeting the nucleotide binding pocket of kinases is the inhibitor residence time. Recently, covalent kinase inhibitors have attracted attention since they confer terminal inhibition and should thus be more effective than reversible inhibitors with transient inhibition. The most robust approach to design irreversible inhibitors is to capitalize on the nucleophilicity of a cysteine thiol group present in the target protein. Herein, we report a systematic analysis of cysteine residues present in the nucleotide binding site of kinases, which could be harnessed for irreversible inhibition, taking into consideration the different kinase conformations. We demonstrate the predictive power of this analysis with the design and validation of an irreversible inhibitor of KIT/PDGFR kinases. This is the first example of a covalent kinase inhibitor that combines a pharmacophore addressing the DFG-out conformation with a covalent trap.