Johan J. N. Veerman; Yorik B. Bruseker; Eddy Damen; Erik H. Heijne; Wendy van Bruggen; Koen F. W. Hekking; Rob Winkel; Christopher D. Hupp; Anthony D. Keefe; Julie Liu; Heather A. Thomson; Ying Zhang; John W. Cuozzo; Andrew J. McRiner; Mark J. Mulvihill; Peter van Rijnsbergen; Birgit Zech; Louis M. Renzetti; Lee Babiss; Gerhard Müller
ACS Med. Chem. Lett., 2021, 12(4), 555-562
https://doi.org/10.1021/acsmedchemlett.0c00547

Abstract

Herein we report the discovery of 2,4-1H-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-2,4-1H-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.