Veerman Johan J N, Bruseker Yorik B, Damen Eddy, Heijne Erik H, van Bruggen Wendy, Hekking Koen F W, Winkel Rob, Hupp Christopher D, Keefe Anthony D, Liu Julie, Thomson Heather A, Zhang Ying, Cuozzo John W, McRiner Andrew J, Mulvihill Mark J, van Rijnsbergen Peter, Zech Birgit, Renzetti Louis M, Babiss Lee, Müller Gerhard
ZoBio BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands.
Mercachem BV, Department of Medicinal Chemistry, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands.
ACS Med Chem Lett. 2021 Mar 3;12(4):555-562. doi: 10.1021/acsmedchemlett.0c00547. eCollection 2021 Apr 8.
Herein we report the discovery of 2,4-1-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor β-activated kinase 1 (TAK1). The target was subjected to a DNA-encoded chemical library (DECL) screen. After hit analysis a cluster of compounds was identified, which was based on a central pyrrole-2,4-1-dicarboxamide scaffold, showing remarkable kinome selectivity. A scaffold-hop to the corresponding imidazole resulted in increased biochemical potency. Next, X-ray crystallography revealed a distinct binding mode compared to other TAK1 inhibitors. A benzylamide was found in a perpendicular orientation with respect to the core hinge-binding imidazole. Additionally, an unusual amide flip was observed in the kinase hinge region. Using structure-based drug design (SBDD), key substitutions at the pyrrolidine amide and the glycine resulted in a significant increase in biochemical potency.
在此，我们报告发现了2,4-1-咪唑甲酰胺类化合物，它们是转化生长因子β激活激酶1（TAK1）的新型、具有强大生化活性且对激酶组具有选择性的抑制剂。对该靶点进行了DNA编码化学文库（DECL）筛选。经过命中分析，鉴定出一组基于中心吡咯-2,4-1-二羧酰胺支架的化合物，它们显示出显著的激酶组选择性。将支架跳跃到相应的咪唑上导致生化活性增强。接下来，X射线晶体学揭示了与其他TAK1抑制剂相比独特的结合模式。发现一个苄基酰胺相对于核心铰链结合咪唑呈垂直取向。此外，在激酶铰链区域观察到一个不寻常的酰胺翻转。使用基于结构的药物设计（SBDD），在吡咯烷酰胺和甘氨酸处进行关键取代导致生化活性显著提高。
