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Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors. 2021
Johan J N Veerman, and
Yorik B Bruseker, and
Eddy Damen, and
Erik H Heijne, and
Wendy van Bruggen, and
Koen F W Hekking, and
Rob Winkel, and
Christopher D Hupp, and
Anthony D Keefe, and
Julie Liu, and
Heather A Thomson, and
Ying Zhang, and
John W Cuozzo, and
Andrew J McRiner, and
Mark J Mulvihill, and
Peter van Rijnsbergen, and
Birgit Zech, and
Louis M Renzetti, and
Lee Babiss, and
Gerhard Müller
ZoBio BV, J.H. Oortweg 19, 2333 CH Leiden, The Netherlands.
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.
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