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ID: ALA4706727
Journal: ACS Med Chem Lett
Title: Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.
Authors: Veerman JJN,Bruseker YB,Damen E,Heijne EH,van Bruggen W,Hekking KFW,Winkel R,Hupp CD,Keefe AD,Liu J,Thomson HA,Zhang Y,Cuozzo JW,McRiner AJ,Mulvihill MJ,van Rijnsbergen P,Zech B,Renzetti LM,Babiss L,Müller G
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.
CiteXplore: 33859795