Faculty of Chemistry and Chemical Biology , TU Dortmund University , Otto-Hahn-Strasse 4a , 44227 Dortmund , Germany.
Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW) , 44227 Dortmund , Germany.
J Med Chem. 2019 Jun 13;62(11):5541-5546. doi: 10.1021/acs.jmedchem.9b00472. Epub 2019 May 31.
Pyrazolopyrimidines are well-established as covalent inhibitors of protein kinases such as the epidermal growth factor receptor or Bruton's tyrosine kinase, and we recently described their potential in targeting mitogen-activated protein kinase kinase 7 (MKK7). Herein, we report the structure-activity relationship of pyrazolopyrimidine-based MKK7 inhibitors and solved several complex crystal structures to gain insights into their binding mode. In addition, we present two structures of apo-MKK7, exhibiting a DFG-out and an unprecedented DFG-in/Leu-in conformation.
吡唑并嘧啶类化合物是一种已被广泛认可的蛋白激酶（如表皮生长因子受体或布鲁顿酪氨酸激酶）的共价抑制剂，我们最近还描述了它们在靶向丝裂原活化蛋白激酶激酶 7（MKK7）方面的潜力。在此，我们报告了基于吡唑并嘧啶的 MKK7 抑制剂的构效关系，并解决了几个复杂的晶体结构，以深入了解其结合模式。此外，我们还展示了 apo-MKK7 的两种结构，分别呈现出 DFG-out 和一种前所未有的 DFG-in/Leu-in 构象。
