7NTH

Structure of TAK1 in complex with compound 54

Summary for 7NTH

• Entry DOI: 10.2210/pdb7nth/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase 7,TGF-beta-activated kinase 1 and MAP3K7-binding protein 1, GLYCEROL, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: kinase, inhibitor, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 36413.84

Authors

Veerman, J.J.N.,Bruseker, Y.B.,Damen, E.,Heijne, E.H.,van Bruggen, W.,Hekking, K.F.W.,Winkel, R.,Hupp, C.D.,Keefe, A.D.,Liu, J.,Thomson, H.A.,Zhang, Y.,Cuozzo, J.W.,McRiner, A.J.,Mulvihill, M.J.,van Rijnsbergen, P.,Zech, B.,Renzetti, L.M.,Babiss, L.,Mueller, G. (deposition date: 2021-03-09, release date: 2021-04-07, Last modification date: 2024-06-19)

Primary citation

Veerman, J.J.N.,Bruseker, Y.B.,Damen, E.,Heijne, E.H.,van Bruggen, W.,Hekking, K.F.W.,Winkel, R.,Hupp, C.D.,Keefe, A.D.,Liu, J.,Thomson, H.A.,Zhang, Y.,Cuozzo, J.W.,McRiner, A.J.,Mulvihill, M.J.,van Rijnsbergen, P.,Zech, B.,Renzetti, L.M.,Babiss, L.,Muller, G.
Discovery of 2,4-1 H -Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.
Acs Med.Chem.Lett., 12:555-562, 2021

PubMed Abstract: 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.

PubMed: 33859795
DOI: 10.1021/acsmedchemlett.0c00547

Experimental method

X-RAY DIFFRACTION (1.97 Å)