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Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.

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.

SUBMITTER: Veerman JJN

PROVIDER: S-EPMC8040042 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.

Veerman Johan J N JJN Bruseker Yorik B YB Damen Eddy E Heijne Erik H EH van Bruggen Wendy W Hekking Koen F W KFW Winkel Rob R Hupp Christopher D CD Keefe Anthony D AD Liu Julie J Thomson Heather A HA Zhang Ying Y Cuozzo John W JW McRiner Andrew J AJ Mulvihill Mark J MJ van Rijnsbergen Peter P Zech Birgit B Renzetti Louis M LM Babiss Lee L Müller Gerhard G

ACS medicinal chemistry letters 20210303 4

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 in ...[more]

PMID: 33859795

Dataset Information

Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.

Publications

Discovery of 2,4-1<i>H</i>-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.

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