Selectivity remains a challenge for ATP-mimetic kinase inhibitors, an issue that may be overcome by targeting unique residues or binding pockets. However, to date only few strategies have been developed. Here we identify that bulky residues located N-terminal to the DFG motif (DFG-1) represent an opportunity for designing highly selective inhibitors with unexpected binding modes. We demonstrate that several diverse inhibitors exerted selective, noncanonical binding modes that exclusively target large hydrophobic DFG-1 residues present in many kinases including PIM, CK1, DAPK, and CLK. By use of the CLK family as a model, structural and biochemical data revealed that the DFG-1 valine controlled a noncanonical binding mode in CLK1, providing a rationale for selectivity over the closely related CLK3 which harbors a smaller DFG-1 alanine. Our data suggest that targeting the restricted back pocket in the small fraction of kinases that harbor bulky DFG-1 residues offers a versatile selectivity filter for inhibitor design.

中文翻译：

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DFG-1残基控制抑制剂的结合模式和亲和力，为激酶抑制剂选择性的合理设计提供了依据。

选择性对于ATP模拟激酶抑制剂仍然是一个挑战，可以通过靶向独特的残基或结合口袋来克服这一问题。然而，迄今为止，仅开发了很少的策略。在这里，我们发现位于DFG基序（DFG-1）N端的庞大残基代表了设计具有意外结合模式的高选择性抑制剂的机会。我们证明了几种不同的抑制剂发挥选择性，非规范的结合模式，专门针对存在于许多激酶（包括PIM，CK1，DAPK和CLK）中的大疏水DFG-1残基。通过使用CLK家族作为模型，结构和生化数据显示DFG-1缬氨酸控制CLK1中的非规范结合模式，从而为具有较小DFG-1丙氨酸的密切相关的CLK3提供了选择依据。