4O91

Crystal Structure of type II inhibitor NG25 bound to TAK1-TAB1

Summary for 4O91

• Entry DOI: 10.2210/pdb4o91/pdb
• Descriptor: Mitogen-activated protein kinase kinase kinase 7/TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 chimera, N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzamide (3 entities in total)
• Functional Keywords: mitogen-activated protein kinase kinase kinase 7, tgf-beta-activated kinase 1 and map3k7-binding protein 1 chimera, serine/threonine kinase which acts as an essential component of the map kinase signal transduction pathway, tgf-beta-activated kinase 1 and map3k7-binding protein 1, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 36001.44

Authors

Gurbani, D.,Hunter, J.C.,Tan, L.,Westover, K.D. (deposition date: 2013-12-31, release date: 2014-07-30, Last modification date: 2024-02-28)

Primary citation

Tan, L.,Nomanbhoy, T.,Gurbani, D.,Patricelli, M.,Hunter, J.,Geng, J.,Herhaus, L.,Zhang, J.,Pauls, E.,Ham, Y.,Choi, H.G.,Xie, T.,Deng, X.,Buhrlage, S.J.,Sim, T.,Cohen, P.,Sapkota, G.,Westover, K.D.,Gray, N.S.
Discovery of Type II Inhibitors of TGF beta-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2).
J.Med.Chem., 58:183-196, 2015

PubMed Abstract: We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure-activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16 and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. A 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.

PubMed: 25075558
DOI: 10.1021/jm500480k

Experimental method

X-RAY DIFFRACTION (2.393 Å)