| Structural highlights
Function
M3K8_HUMAN Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the proinflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chemical optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFalpha. Pharmacological profiling in vivo revealed a high metabolism of these compounds in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compounds both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases.
Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors.,Glatthar R, Stojanovic A, Troxler T, Mattes H, Mobitz H, Beerli R, Blanz J, Gassmann E, Druckes P, Fendrich G, Gutmann S, Martiny-Baron G, Spence F, Hornfeld J, Peel JE, Sparrer H J Med Chem. 2016 Aug 25;59(16):7544-60. doi: 10.1021/acs.jmedchem.6b00598. Epub, 2016 Aug 17. PMID:27502541[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Velasco-Sampayo A, Alemany S. p27kip protein levels and E2F activity are targets of Cot kinase during G1 phase progression in T cells. J Immunol. 2001 May 15;166(10):6084-90. PMID:11342626
- ↑ Waterfield MR, Zhang M, Norman LP, Sun SC. NF-kappaB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the Tpl2 kinase. Mol Cell. 2003 Mar;11(3):685-94. PMID:12667451
- ↑ Lang V, Symons A, Watton SJ, Janzen J, Soneji Y, Beinke S, Howell S, Ley SC. ABIN-2 forms a ternary complex with TPL-2 and NF-kappa B1 p105 and is essential for TPL-2 protein stability. Mol Cell Biol. 2004 Jun;24(12):5235-48. PMID:15169888 doi:http://dx.doi.org/10.1128/MCB.24.12.5235-5248.2004
- ↑ Rodriguez C, Pozo M, Nieto E, Fernandez M, Alemany S. TRAF6 and Src kinase activity regulates Cot activation by IL-1. Cell Signal. 2006 Sep;18(9):1376-85. Epub 2005 Dec 20. PMID:16371247 doi:http://dx.doi.org/10.1016/j.cellsig.2005.10.016
- ↑ Aoki M, Akiyama T, Miyoshi J, Toyoshima K. Identification and characterization of protein products of the cot oncogene with serine kinase activity. Oncogene. 1991 Sep;6(9):1515-9. PMID:1833717
- ↑ Watford WT, Hissong BD, Durant LR, Yamane H, Muul LM, Kanno Y, Tato CM, Ramos HL, Berger AE, Mielke L, Pesu M, Solomon B, Frucht DM, Paul WE, Sher A, Jankovic D, Tsichlis PN, O'Shea JJ. Tpl2 kinase regulates T cell interferon-gamma production and host resistance to Toxoplasma gondii. J Exp Med. 2008 Nov 24;205(12):2803-12. doi: 10.1084/jem.20081461. Epub 2008 Nov , 10. PMID:19001140 doi:http://dx.doi.org/10.1084/jem.20081461
- ↑ Handoyo H, Stafford MJ, McManus E, Baltzis D, Peggie M, Cohen P. IRAK1-independent pathways required for the interleukin-1-stimulated activation of the Tpl2 catalytic subunit and its dissociation from ABIN2. Biochem J. 2009 Oct 23;424(1):109-18. doi: 10.1042/BJ20091271. PMID:19754427 doi:http://dx.doi.org/10.1042/BJ20091271
- ↑ Jager J, Gremeaux T, Gonzalez T, Bonnafous S, Debard C, Laville M, Vidal H, Tran A, Gual P, Le Marchand-Brustel Y, Cormont M, Tanti JF. Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate interleukin-1beta and tumor necrosis factor-{alpha} effects on extracellular signal-regulated kinase activation and lipolysis. Diabetes. 2010 Jan;59(1):61-70. doi: 10.2337/db09-0470. Epub 2009 Oct 6. PMID:19808894 doi:http://dx.doi.org/10.2337/db09-0470
- ↑ Glatthar R, Stojanovic A, Troxler T, Mattes H, Mobitz H, Beerli R, Blanz J, Gassmann E, Druckes P, Fendrich G, Gutmann S, Martiny-Baron G, Spence F, Hornfeld J, Peel JE, Sparrer H. Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors. J Med Chem. 2016 Aug 25;59(16):7544-60. doi: 10.1021/acs.jmedchem.6b00598. Epub, 2016 Aug 17. PMID:27502541 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00598
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