Download all structure-activity data for this target as a CSV file Description: In a Kinobeads assay using lysates from HEK293/K-562/Placenta/HepG2 cells. EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1 M and 10 M against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5 M against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform. http://www.millipore.com/techpublications/tech1/pf3036 http://www.reactionbiology.com/webapps/main/pages/kinase.aspx TBK1 belongs to the IKK-kinase family of enzymes. It is a ubiquitously expressed serine/threonine protein kinase, and constitutes a key regulatory node for several signaling pathways involved in the innate immune response that lead to induction of type I interferons. Several classes of innate sensors including the TLRs and retinoic acid-inducible gene 1 (RIG-I)-like helicases engage TBK1-IRF3 signaling pathways to regulate transcription of type I IFNs. In neuroinflammation TBK1 is involved in TLR-dependent [11] and -independent responses [5]. DNA sensing receptors such as DAI, IFI16, DDX41, and cGAS have all been shown to couple dsDNA recognition to TBK1 activation. STING is a critical mediator of DNA-induced TBK1 activation. Dysregulation of TBK1 activity is associated with autoimmune diseases and cancer, conditions which may be amenable to pharmacological inhibition of TBK1 [10]. Inhibition of TBK1 can also be considered in the context of the so-called type I interferonopathies, a set of rare autoimmune pathologies associated with chronic activation of IFN I responses [13]. Physiological Consequences of Altering Gene Expression TBK1 ablation in mice is embryonic lethal. They die at stage E14.5 due to liver degeneration and apoptosis. Clinically-Relevant Mutations and Pathophysiology Synonyms: Herpes simplex encephalitisHerpes simplex virus encephalitis [Disease Ontology: DOID:0050181]HSV encephalitis Genetic mutations in TBK1 (e.g. increased TBK1 copy number resulting in a gain of function) is a rare cause of primary open angle glaucoma and normal tension glaucoma. Heterozygous loss of function TBK1 mutations are associated with herpes simplex encephalitis in childhood. Both of these associations are to diseases with neuroinflammatory components. TBK1 has now been identified by several studies as an amyotrophic lateral sclerosis (ALS) gene [3,8,24], often in comorbidity with frontotemporal dementia (FTD) [12,19]. TBK1 and IKKε phosphorylate the transcription factors interferon (IFN) regulator factor (IRF) 3 and 7. This function is critical for the induction of the type I IFN response (induction of IFN genes and IFN-stimulated genes) in response to microbial infection [7,21]. 1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR.(2011)Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. 2. Bonnard M, Mirtsos C, Suzuki S, Graham K, Huang J, Ng M, Itié A, Wakeham A, Shahinian A, Henzel WJ et al..(2000)Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription. 3. Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ et al..(2015)Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. 4. Clark K, Peggie M, Plater L, Sorcek RJ, Young ER, Madwed JB, Hough J, McIver EG, Cohen P.(2011)Novel cross-talk within the IKK family controls innate immunity. 5. Cui J, Chen Y, Wang HY, Wang RF.(2014)Mechanisms and pathways of innate immune activation and regulation in health and cancer. 6. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP.(2011)Comprehensive analysis of kinase inhibitor selectivity. 7. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T.(2003)IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. 8. Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Müller K, Marroquin N, Nordin F, Hübers A, Weydt P et al..(2015)Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. 9. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ.(2013)A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. 10. Hasan M, Yan N.(2016)Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies. 11. Kawai T, Akira S.(2007)Signaling to NF-kappaB by Toll-like receptors. 12. Le Ber I, De Septenville A, Millecamps S, Camuzat A, Caroppo P, Couratier P, Blanc F, Lacomblez L, Sellal F, Fleury MC et al..(2015)TBK1 mutation frequencies in French frontotemporal dementia and amyotrophic lateral sclerosis cohorts. 14. Lefranc J, Schulze VK, Hillig RC, Briem H, Prinz F, Mengel A, Heinrich T, Balint J, Rengachari S, Irlbacher H et al..(2020)Discovery of BAY-985, a Highly Selective TBK1/IKKε Inhibitor. 15. Li J, Huang J, Jeong JH, Park SJ, Wei R, Peng J, Luo Z, Chen YT, Feng Y, Luo JL.(2014)Selective TBK1/IKKi dual inhibitors with anticancer potency. 16. McIver EG, Bryans J, Birchall K, Chugh J, Drake T, Lewis SJ, Osborne J, Smiljanic-Hurley E, Tsang W, Kamal A et al..(2012)Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases. 17. Ou YH, Torres M, Ram R, Formstecher E, Roland C, Cheng T, Brekken R, Wurz R, Tasker A, Polverino T et al..(2011)TBK1 directly engages Akt/PKB survival signaling to support oncogenic transformation. 18. Perrior TR, Newton GK, Stewart MR, Aqil R.(2012)Pyrimidine compounds as inhibitors of protein kinases ikk epsilon and/or tbk-1, processes for their preparation, and pharmaceutical compositions containing them. Patent number: WO2012010826. Assignee: Domainex Limited.Priority date: 19/07/2010. Publication date: 26/01/2012.19. Pottier C, Bieniek KF, Finch N, van de Vorst M, Baker M, Perkersen R, Brown P, Ravenscroft T, van Blitterswijk M, Nicholson AM et al..(2015)Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. 20. Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, Rubin JR, Mowers J, White NM, Hochberg I et al..(2013)An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice. 21. Sankar S, Chan H, Romanow WJ, Li J, Bates RJ.(2006)IKK-i signals through IRF3 and NFkappaB to mediate the production of inflammatory cytokines. 22. Thomson DW, Poeckel D, Zinn N, Rau C, Strohmer K, Wagner AJ, Graves AP, Perrin J, Bantscheff M, Duempelfeld B et al..(2019)Discovery of GSK8612, a Highly Selective and Potent TBK1 Inhibitor. 23. Vu HL, Aplin AE.(2014)Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma. 24. Williams KL, McCann EP, Fifita JA, Zhang K, Duncan EL, Leo PJ, Marshall M, Rowe DB, Nicholson GA, Blair IP.(2015)Novel TBK1 truncating mutation in a familial amyotrophic lateral sclerosis patient of Chinese origin. 25. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al..(2010)Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. IKK family: TANK binding kinase 1. Last modified on 15/01/2020. Accessed on 18/05/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2237.