7nth
From Proteopedia
Structure of TAK1 in complex with compound 54
Structural highlights
Function[M3K7_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedHerein we report the discovery of 2,4-1H-imidazole carboxamides as novel, biochemically potent, and kinome selective inhibitors of transforming growth factor beta-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. Discovery of 2,4-1H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors.,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, Muller G ACS Med Chem Lett. 2021 Mar 3;12(4):555-562. doi: 10.1021/acsmedchemlett.0c00547., eCollection 2021 Apr 8. PMID:33859795[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Mitogen-activated protein kinase kinase kinase | Babiss, L | Bruggen, W van | Bruseker, Y B | Cuozzo, J W | Damen, E | Heijne, E H | Hekking, K F.W | Hupp, C D | Keefe, A D | Liu, J | McRiner, A J | Mueller, G | Mulvihill, M J | Renzetti, L M | Rijnsbergen, P van | Thomson, H A | Veerman, J J.N | Winkel, R | Zech, B | Zhang, Y | Inhibitor | Kinase | Transferase
