Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max von Lauestraße 9, 60438 Frankfurt, Germany.
Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe-University Frankfurt, Max von Lauestraße 15, 60438 Frankfurt, Germany.
J Med Chem. 2020 Sep 24;63(18):10224-10234. doi: 10.1021/acs.jmedchem.0c00898. Epub 2020 Aug 27.
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.
选择性仍然是 ATP 模拟激酶抑制剂的一个挑战，这个问题可能通过针对独特的残基或结合口袋来解决。然而，迄今为止，只有少数几种策略得到了发展。在这里，我们发现位于 DFG 基序（DFG-1）N 端的大体积残基为设计具有意想不到的结合模式的高度选择性抑制剂提供了机会。我们证明了几种不同的抑制剂具有选择性的、非典型的结合模式，这些抑制剂专门针对许多激酶中存在的大疏水性 DFG-1 残基，包括 PIM、CK1、DAPK 和 CLK。通过使用 CLK 家族作为模型，结构和生化数据表明，DFG-1 缬氨酸控制 CLK1 中的非典型结合模式，为 CLK1 提供了选择性的理由，而与 CLK3 相比，CLK3 具有较小的 DFG-1 丙氨酸。我们的数据表明，针对那些含有大体积 DFG-1 残基的激酶中的一小部分限制后口袋，为抑制剂设计提供了一种通用的选择性过滤器。
