Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Role of TBK1 Inhibition in Targeted Therapy of Cancer

Author(s): Xueqing Yang and Zongliang Liu*

Volume 24, Issue 10, 2024

Published on: 16 January, 2024

Page: [1031 - 1045] Pages: 15

DOI: 10.2174/0113895575271977231115062803

Price: $65

Abstract

TANK-binding kinase 1 (TBK1) is a serine/threonine protein that plays a crucial role in various biological processes like immunity, autophagy, cell survival, and proliferation. The level and kinase activity of the TBK1 protein is regulated through post-translational modifications (PTMs). TBK1 mainly mediates the activation of IRF3/7 and NF-κB signaling pathways while also participating in the regulation of cellular activities such as autophagy, mitochondrial metabolism, and cell proliferation. TBK1 regulates immune, metabolic, inflammatory, and tumor occurrence and development within the body through these cellular activities. TBK1 kinase has emerged as a promising therapeutic target for tumor immunity. However, its molecular mechanism of action remains largely unknown. The identification of selective TBK1 small molecule inhibitors can serve as valuable tools for investigating the biological function of TBK1 protein and also as potential drug candidates for tumor immunotherapy. The current research progress indicates that some TBK1 inhibitors (compounds 15,16 and 21) exhibit certain antitumor effects in vitro culture systems. Here, we summarize the mechanism of action of TBK1 in tumors in recent years and the progress of small molecule inhibitors of TBK1.

« Previous Next »
Graphical Abstract

[1]
Kruger, S.; Ilmer, M.; Kobold, S.; Cadilha, B.L.; Endres, S.; Ormanns, S.; Schuebbe, G.; Renz, B.W.; D’Haese, J.G.; Schloesser, H.; Heinemann, V.; Subklewe, M.; Boeck, S.; Werner, J.; von Bergwelt-Baildon, M. Advances in cancer immunotherapy 2019 – latest trends. J. Exp. Clin. Cancer Res., 2019, 38(1), 268.
[http://dx.doi.org/10.1186/s13046-019-1266-0] [PMID: 31217020]
[2]
Darvin, P.; Toor, S.M.; Sasidharan Nair, V.; Elkord, E. Immune checkpoint inhibitors: Recent progress and potential biomarkers. Exp. Mol. Med., 2018, 50(12), 1-11.
[http://dx.doi.org/10.1038/s12276-018-0191-1] [PMID: 30546008]
[3]
Barber, G.N. STING: Infection, inflammation and cancer. Nat. Rev. Immunol., 2015, 15(12), 760-770.
[http://dx.doi.org/10.1038/nri3921] [PMID: 26603901]
[4]
Xu, J.; Jia, Y.F.; Tapadar, S.; Weaver, J.D.; Raji, I.O.; Pithadia, D.J.; Javeed, N.; García, A.J.; Choi, D.S.; Matveyenko, A.V.; Oyelere, A.K.; Shin, C.H. Inhibition of TBK1/IKKε promotes regeneration of pancreatic β-cells. Sci. Rep., 2018, 8(1), 15587.
[http://dx.doi.org/10.1038/s41598-018-33875-0] [PMID: 30349097]
[5]
Weidberg, H.; Elazar, Z. TBK1 mediates crosstalk between the innate immune response and autophagy. Sci. Signal., 2011, 4(187), pe39.
[http://dx.doi.org/10.1126/scisignal.2002355] [PMID: 21868362]
[6]
Hasan, M.; Dobbs, N.; Khan, S.; White, M.A.; Wakeland, E.K.; Li, Q.Z.; Yan, N. Cutting edge: Inhibiting TBK1 by compound II ameliorates autoimmune disease in mice. J. Immunol., 2015, 195(10), 4573-4577.
[http://dx.doi.org/10.4049/jimmunol.1500162] [PMID: 26432890]
[7]
Hammaker, D.; Boyle, D.L.; Firestein, G.S. Synoviocyte innate immune responses: TANK-binding kinase-1 as a potential therapeutic target in Rheumatoid arthritis. Rheumatology, 2012, 51(4), 610-618.
[http://dx.doi.org/10.1093/rheumatology/ker154] [PMID: 21613249]
[8]
Hasan, M.; Yan, N. Therapeutic potential of targeting TBK1 in autoimmune diseases and interferonopathies. Pharmacol. Res., 2016, 111, 336-342.
[http://dx.doi.org/10.1016/j.phrs.2016.04.008] [PMID: 27353409]
[9]
Jung, H.R.; Jo, S.; Jeon, M.J.; Lee, H.; Chu, Y.; Lee, J.; Kim, E.; Song, G.Y.; Jung, C.; Kim, H.; Lee, S. Development of small-molecule sting activators for cancer immunotherapy. Biomedicines, 2021, 10(1), 33.
[http://dx.doi.org/10.3390/biomedicines10010033] [PMID: 35052713]
[10]
Xiang, S.; Song, S.; Tang, H.; Smaill, J.B.; Wang, A.; Xie, H.; Lu, X. TANK-binding kinase 1 (TBK1): An emerging therapeutic target for drug discovery. Drug Discov. Today, 2021, 26(10), 2445-2455.
[http://dx.doi.org/10.1016/j.drudis.2021.05.016] [PMID: 34051368]
[11]
Runde, A.P.; Mack, R.; S J, P.B.; Zhang, J. The role of TBK1 in cancer pathogenesis and anticancer immunity. J. Exp. Clin. Cancer Res., 2022, 41(1), 135.
[http://dx.doi.org/10.1186/s13046-022-02352-y] [PMID: 35395857]
[12]
Pomerantz, J.L.; Baltimore, D. NF-kappa B activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase. EMBO J., 1999, 18(23), 6694-6704.
[http://dx.doi.org/10.1093/emboj/18.23.6694] [PMID: 10581243]
[13]
Yu, T.; Yi, Y.S.; Yang, Y.; Oh, J.; Jeong, D.; Cho, J.Y. The pivotal role of TBK1 in inflammatory responses mediated by macrophages. Mediators Inflamm., 2012, 2012, 1-8.
[http://dx.doi.org/10.1155/2012/979105] [PMID: 23304064]
[14]
Li, J.; Li, J.; Miyahira, A.; Sun, J.; Liu, Y.; Cheng, G.; Liang, H. Crystal structure of the ubiquitin-like domain of human TBK1. Protein Cell, 2012, 3(5), 383-391.
[http://dx.doi.org/10.1007/s13238-012-2929-1] [PMID: 22610919]
[15]
Ma, X.; Helgason, E.; Phung, Q.T.; Quan, C.L.; Iyer, R.S.; Lee, M.W.; Bowman, K.K.; Starovasnik, M.A.; Dueber, E.C. Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation. Proc. Natl. Acad. Sci., 2012, 109(24), 9378-9383.
[http://dx.doi.org/10.1073/pnas.1121552109] [PMID: 22619329]
[16]
Larabi, A.; Devos, J.M.; Ng, S.L.; Nanao, M.H.; Round, A.; Maniatis, T.; Panne, D. Crystal structure and mechanism of activation of TANK-binding kinase 1. Cell Rep., 2013, 3(3), 734-746.
[http://dx.doi.org/10.1016/j.celrep.2013.01.034] [PMID: 23453971]
[17]
Tu, D.; Zhu, Z.; Zhou, A.Y.; Yun, C.; Lee, K.E.; Toms, A.V.; Li, Y.; Dunn, G.P.; Chan, E.; Thai, T.; Yang, S.; Ficarro, S.B.; Marto, J.A.; Jeon, H.; Hahn, W.C.; Barbie, D.A.; Eck, M.J. Structure and ubiquitination-dependent activation of TANK-binding kinase 1. Cell Rep., 2013, 3(3), 747-758.
[http://dx.doi.org/10.1016/j.celrep.2013.01.033] [PMID: 23453972]
[18]
Fitzgerald, K.A.; McWhirter, S.M.; Faia, K.L.; Rowe, D.C.; Latz, E.; Golenbock, D.T.; Coyle, A.J.; Liao, S.M.; Maniatis, T. IKKε and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol., 2003, 4(5), 491-496.
[http://dx.doi.org/10.1038/ni921] [PMID: 12692549]
[19]
Zhao, C.; Zhao, W. TANK-binding kinase 1 as a novel therapeutic target for viral diseases. Expert Opin. Ther. Targets, 2019, 23(5), 437-446.
[http://dx.doi.org/10.1080/14728222.2019.1601702] [PMID: 30932713]
[20]
Zhao, B.; Du, F.; Xu, P.; Shu, C.; Sankaran, B.; Bell, S.L.; Liu, M.; Lei, Y.; Gao, X.; Fu, X.; Zhu, F.; Liu, Y.; Laganowsky, A.; Zheng, X.; Ji, J.Y.; West, A.P.; Watson, R.O.; Li, P. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Nature, 2019, 569(7758), 718-722.
[http://dx.doi.org/10.1038/s41586-019-1228-x] [PMID: 31118511]
[21]
Jiang, M.; Chen, P.; Wang, L.; Li, W.; Chen, B.; Liu, Y.; Wang, H.; Zhao, S.; Ye, L.; He, Y.; Zhou, C. cGAS-STING, an important pathway in cancer immunotherapy. J. Hematol. Oncol., 2020, 13(1), 81.
[http://dx.doi.org/10.1186/s13045-020-00916-z] [PMID: 32571374]
[22]
Gu, M.; Liu, Z.; Lai, R.; Liu, S.; Lin, W.; Ouyang, C.; Ye, S.; Huang, H.; Wang, X. RKIP and TBK 1 form a positive feedback loop to promote type I interferon production in innate immunity. EMBO J., 2016, 35(23), 2553-2565.
[http://dx.doi.org/10.15252/embj.201694060] [PMID: 27753621]
[23]
Ma, C.; Lin, W.; Liu, Z.; Tang, W.; Gautam, R.; Li, H.; Qian, Y.; Huang, H.; Wang, X. NDR 1 protein kinase promotes IL ‐17‐ and TNF ‐α‐mediated inflammation by competitively binding TRAF 3. EMBO Rep., 2017, 18(4), 586-602.
[http://dx.doi.org/10.15252/embr.201642140] [PMID: 28219902]
[24]
Mori, M.; Yoneyama, M.; Ito, T.; Takahashi, K.; Inagaki, F.; Fujita, T. Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation. J. Biol. Chem., 2004, 279(11), 9698-9702.
[http://dx.doi.org/10.1074/jbc.M310616200] [PMID: 14703513]
[25]
Chen, W.; Srinath, H.; Lam, S.S.; Schiffer, C.A.; Royer, W.E., Jr; Lin, K. Contribution of Ser386 and Ser396 to activation of interferon regulatory factor 3. J. Mol. Biol., 2008, 379(2), 251-260.
[http://dx.doi.org/10.1016/j.jmb.2008.03.050] [PMID: 18440553]
[26]
Caillaud, A.; Hovanessian, A.G.; Levy, D.E.; Marié, I.J. Regulatory serine residues mediate phosphorylation-dependent and phosphorylation-independent activation of interferon regulatory factor 7. J. Biol. Chem., 2005, 280(18), 17671-17677.
[http://dx.doi.org/10.1074/jbc.M411389200] [PMID: 15743772]
[27]
Xiao, Y.; Zou, Q.; Xie, X.; Liu, T.; Li, H.S.; Jie, Z.; Jin, J.; Hu, H.; Manyam, G.; Zhang, L.; Cheng, X.; Wang, H.; Marie, I.; Levy, D.E.; Watowich, S.S.; Sun, S.C. The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity. J. Exp. Med., 2017, 214(5), 1493-1507.
[http://dx.doi.org/10.1084/jem.20161524] [PMID: 28356390]
[28]
Chen, H.; Sun, H.; You, F.; Sun, W.; Zhou, X.; Chen, L.; Yang, J.; Wang, Y.; Tang, H.; Guan, Y.; Xia, W.; Gu, J.; Ishikawa, H.; Gutman, D.; Barber, G.; Qin, Z.; Jiang, Z. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell, 2011, 147(2), 436-446.
[http://dx.doi.org/10.1016/j.cell.2011.09.022] [PMID: 22000020]
[29]
Tojima, Y.; Fujimoto, A.; Delhase, M.; Chen, Y.; Hatakeyama, S.; Nakayama, K.; Kaneko, Y.; Nimura, Y.; Motoyama, N.; Ikeda, K.; Karin, M.; Nakanishi, M. NAK is an IκB kinase-activating kinase. Nature, 2000, 404(6779), 778-782.
[http://dx.doi.org/10.1038/35008109] [PMID: 10783893]
[30]
Lork, M.; Kreike, M.; Staal, J.; Beyaert, R.; Biology, D. Importance of validating antibodies and small compound inhibitors using genetic knockout studies—T cell receptor-induced CYLD phosphorylation by IKKε/TBK1 as a case study. Front. Cell Dev. Biol., 2018, 6, 40.
[http://dx.doi.org/10.3389/fcell.2018.00040] [PMID: 29755980]
[31]
Buss, H.; Dörrie, A.; Schmitz, M.L.; Hoffmann, E.; Resch, K.; Kracht, M. Constitutive and interleukin-1-inducible phosphorylation of p65 NF-κB at serine 536 is mediated by multiple protein kinases including IκB kinase (IKK)-α, IKKβ, IKKϵ, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. J. Biol. Chem., 2004, 279(53), 55633-55643.
[http://dx.doi.org/10.1074/jbc.M409825200] [PMID: 15489227]
[32]
Fujita, F.; Taniguchi, Y.; Kato, T.; Narita, Y.; Furuya, A.; Ogawa, T.; Sakurai, H.; Joh, T.; Itoh, M.; Delhase, M.; Karin, M.; Nakanishi, M. Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling. Mol. Cell. Biol., 2003, 23(21), 7780-7793.
[http://dx.doi.org/10.1128/MCB.23.21.7780-7793.2003] [PMID: 14560022]
[33]
Bonnard, M.; Mirtsos, C.; Suzuki, S.; Graham, K.; Huang, J.; Ng, M.; Itié, A.; Wakeham, A.; Shahinian, A.; Henzel, W.J.; Elia, A.J.; Shillinglaw, W.; Mak, T.W.; Cao, Z.; Yeh, W.C. Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription. EMBO J., 2000, 19(18), 4976-4985.
[http://dx.doi.org/10.1093/emboj/19.18.4976] [PMID: 10990461]
[34]
Pillai, S.; Nguyen, J.; Johnson, J.; Haura, E.; Coppola, D.; Chellappan, S. Tank binding kinase 1 is a centrosome-associated kinase necessary for microtubule dynamics and mitosis. Nat. Commun., 2015, 6(1), 10072.
[http://dx.doi.org/10.1038/ncomms10072] [PMID: 26656453]
[35]
Yu, J.; Zhou, X.; Chang, M.; Nakaya, M.; Chang, J.H.; Xiao, Y.; William Lindsey, J.; Dorta-Estremera, S.; Cao, W.; Zal, A.; Zal, T.; Sun, S.C. Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nat. Commun., 2015, 6(1), 6074.
[http://dx.doi.org/10.1038/ncomms7074] [PMID: 25606824]
[36]
Bodur, C.; Kazyken, D.; Huang, K.; Ekim Ustunel, B.; Siroky, K.A.; Tooley, A.S.; Gonzalez, I.E.; Foley, D.H.; Acosta-Jaquez, H.A.; Barnes, T.M.; Steinl, G.K.; Cho, K.W.; Lumeng, C.N.; Riddle, S.M.; Myers, M.G., Jr; Fingar, D.C. The IKK‐related kinase TBK1 activates mTORC1 directly in response to growth factors and innate immune agonists. EMBO J., 2018, 37(1), 19-38.
[http://dx.doi.org/10.15252/embj.201696164] [PMID: 29150432]
[37]
Tooley, A.S.; Kazyken, D.; Bodur, C.; Gonzalez, I.E.; Fingar, D.C. The innate immune kinase TBK1 directly increases mTORC2 activity and downstream signaling to Akt. J. Biol. Chem., 2021, 297(2), 100942.
[http://dx.doi.org/10.1016/j.jbc.2021.100942] [PMID: 34245780]
[38]
Cooper, J.M.; Ou, Y.H.; McMillan, E.A.; Vaden, R.M.; Zaman, A.; Bodemann, B.O.; Makkar, G.; Posner, B.A.; White, M.A. TBK1 provides context-selective support of the activated akt/mtor pathway in lung cancer. Cancer Res., 2017, 77(18), 5077-5094.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-0829] [PMID: 28716898]
[39]
Zhao, P.; Wong, K.; Sun, X.; Reilly, S.M.; Uhm, M.; Liao, Z.; Skorobogatko, Y.; Saltiel, A.R. TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue. Cell, 2018, 172(4), 731-743.e12.
[http://dx.doi.org/10.1016/j.cell.2018.01.007] [PMID: 29425491]
[40]
Herhaus, L.; Bhaskara, R.M.; Lystad, A.H.; Gestal-Mato, U.; Covarrubias-Pinto, A.; Bonn, F.; Simonsen, A.; Hummer, G.; Dikic, I. TBK1‐mediated phosphorylation of LC3C and GABARAP‐L2 controls autophagosome shedding by ATG4 protease. EMBO Rep., 2020, 21(1), e48317.
[http://dx.doi.org/10.15252/embr.201948317] [PMID: 31709703]
[41]
Pilli, M.; Arko-Mensah, J.; Ponpuak, M.; Roberts, E.; Master, S.; Mandell, M.A.; Dupont, N.; Ornatowski, W.; Jiang, S.; Bradfute, S.B.; Bruun, J.A.; Hansen, T.E.; Johansen, T.; Deretic, V. TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity, 2012, 37(2), 223-234.
[http://dx.doi.org/10.1016/j.immuni.2012.04.015] [PMID: 22921120]
[42]
Heo, J.M.; Ordureau, A.; Swarup, S.; Paulo, J.A.; Shen, K.; Sabatini, D.M.; Harper, J.W. RAB7A phosphorylation by TBK1 promotes mitophagy via the PINK-PARKIN pathway. Sci. Adv., 2018, 4(11), eaav0443.
[http://dx.doi.org/10.1126/sciadv.aav0443] [PMID: 30627666]
[43]
Wild, P.; Farhan, H.; McEwan, D.G.; Wagner, S.; Rogov, V.V.; Brady, N.R.; Richter, B.; Korac, J.; Waidmann, O.; Choudhary, C.; Dötsch, V.; Bumann, D.; Dikic, I. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science, 2011, 333(6039), 228-233.
[http://dx.doi.org/10.1126/science.1205405] [PMID: 21617041]
[44]
Brubaker, S.W.; Bonham, K.S.; Zanoni, I.; Kagan, J.C. Innate immune pattern recognition: A cell biological perspective. Annu. Rev. Immunol., 2015, 33(1), 257-290.
[http://dx.doi.org/10.1146/annurev-immunol-032414-112240] [PMID: 25581309]
[45]
Hu, Y.; Li, X.; Wang, D.; Mao, X. mascRNA alleviates STING-TBK1 signaling-mediated immune response through promoting ubiquitination of STING. Mol. Immunol., 2023, 154, 45-53.
[http://dx.doi.org/10.1016/j.molimm.2022.12.012] [PMID: 36603304]
[46]
Boxx, G.M.; Cheng, G. The roles of type I interferon in bacterial infection. Cell Host Microbe, 2016, 19(6), 760-769.
[http://dx.doi.org/10.1016/j.chom.2016.05.016] [PMID: 27281568]
[47]
Zhang, C.; Shang, G.; Gui, X.; Zhang, X.; Bai, X.; Chen, Z.J. Structural basis of STING binding with and phosphorylation by TBK1. Nature, 2019, 567(7748), 394-398.
[http://dx.doi.org/10.1038/s41586-019-1000-2] [PMID: 30842653]
[48]
Pimkova Polidarova, M.; Brehova, P.; Dejmek, M.; Birkus, G.; Brazdova, A. STING agonist-mediated cytokine secretion is accompanied by monocyte apoptosis. ACS Infect. Dis., 2022, 8(3), 463-471.
[http://dx.doi.org/10.1021/acsinfecdis.1c00554] [PMID: 35132859]
[49]
Dempsey, A.; Bowie, A.G. Innate immune recognition of DNA: A recent history. Virology, 2015, 479-480, 146-152.
[http://dx.doi.org/10.1016/j.virol.2015.03.013] [PMID: 25816762]
[50]
Ritchie, C.; Carozza, J.A.; Li, L. Biochemistry, Cell Biology, and Pathophysiology of the Innate Immune cGAS–cGAMP–STING Pathway. Annu. Rev. Biochem., 2022, 91(1), 599-628.
[http://dx.doi.org/10.1146/annurev-biochem-040320-101629] [PMID: 35287475]
[51]
Ding, C.; Song, Z.; Shen, A.; Chen, T.; Zhang, A. Small molecules targeting the innate immune cGAS‒STING‒TBK1 signaling pathway. Acta Pharm. Sin. B, 2020, 10(12), 2272-2298.
[http://dx.doi.org/10.1016/j.apsb.2020.03.001] [PMID: 33354501]
[52]
Cai, X.; Chiu, Y.H.; Chen, Z.J. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol. Cell, 2014, 54(2), 289-296.
[http://dx.doi.org/10.1016/j.molcel.2014.03.040] [PMID: 24766893]
[53]
Levine, B.; Klionsky, D.J. Development by self-digestion. Dev. Cell, 2004, 6(4), 463-477.
[http://dx.doi.org/10.1016/S1534-5807(04)00099-1] [PMID: 15068787]
[54]
Yu, L.; Chen, Y.; Tooze, S.A. Autophagy pathway: Cellular and molecular mechanisms. Autophagy, 2018, 14(2), 207-215.
[http://dx.doi.org/10.1080/15548627.2017.1378838] [PMID: 28933638]
[55]
Herhaus, L. TBK1 (TANK-binding kinase 1)-mediated regulation of autophagy in health and disease. Matrix Biol., 2021, 100-101, 84-98.
[http://dx.doi.org/10.1016/j.matbio.2021.01.004] [PMID: 33454423]
[56]
Rybstein, M.D.; Bravo-San Pedro, J.M.; Kroemer, G.; Galluzzi, L. The autophagic network and cancer. Nat. Cell Biol., 2018, 20(3), 243-251.
[http://dx.doi.org/10.1038/s41556-018-0042-2] [PMID: 29476153]
[57]
Wan, W.; Qian, C.; Wang, Q.; Li, J.; Zhang, H.; Wang, L.; Pu, M.; Huang, Y.; He, Z.; Zhou, T.; Shen, H.M.; Liu, W. STING directly recruits WIPI2 for autophagosome formation during STING‐induced autophagy. EMBO J., 2023, 42(8), e112387.
[http://dx.doi.org/10.15252/embj.2022112387] [PMID: 36872914]
[58]
Oakes, J.A.; Davies, M.C.; Collins, M.O. TBK1: A new player in ALS linking autophagy and neuroinflammation. Mol. Brain, 2017, 10(1), 5.
[http://dx.doi.org/10.1186/s13041-017-0287-x] [PMID: 28148298]
[59]
Weishaupt, J.H.; Hyman, T.; Dikic, I. Common molecular pathways in amyotrophic lateral sclerosis and frontotemporal dementia. Trends Mol. Med., 2016, 22(9), 769-783.
[http://dx.doi.org/10.1016/j.molmed.2016.07.005] [PMID: 27498188]
[60]
Harding, O.; Evans, C.S.; Ye, J.; Cheung, J.; Maniatis, T.; Holzbaur, E.L.F. ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy. Proc. Natl. Acad. Sci., 2021, 118(24), e2025053118.
[http://dx.doi.org/10.1073/pnas.2025053118] [PMID: 34099552]
[61]
Sato, M.; Sato, K.; Tomura, K.; Kosako, H.; Sato, K. The autophagy receptor ALLO-1 and the IKKE-1 kinase control clearance of paternal mitochondria in Caenorhabditis elegans. Nat. Cell Biol., 2018, 20(1), 81-91.
[http://dx.doi.org/10.1038/s41556-017-0008-9] [PMID: 29255173]
[62]
Kim, J.Y.; Welsh, E.A.; Oguz, U.; Fang, B.; Bai, Y.; Kinose, F.; Bronk, C.; Remsing Rix, L.L.; Beg, A.A.; Rix, U.; Eschrich, S.A.; Koomen, J.M.; Haura, E.B. Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells. Proc. Natl. Acad. Sci., 2013, 110(30), 12414-12419.
[http://dx.doi.org/10.1073/pnas.1220674110] [PMID: 23836654]
[63]
Dikic, I.; Johansen, T.; Kirkin, V. Selective autophagy in cancer development and therapy. Cancer Res., 2010, 70(9), 3431-3434.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-4027] [PMID: 20424122]
[64]
Chien, Y.; Kim, S.; Bumeister, R.; Loo, Y.M.; Kwon, S.W.; Johnson, C.L.; Balakireva, M.G.; Romeo, Y.; Kopelovich, L.; Gale, M., Jr; Yeaman, C.; Camonis, J.H.; Zhao, Y.; White, M.A.; Ral, B.; Ral, B. GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell, 2006, 127(1), 157-170.
[http://dx.doi.org/10.1016/j.cell.2006.08.034] [PMID: 17018283]
[65]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[66]
Sun, Y.; Revach, O.; Anderson, S.; Kessler, E.A.; Wolfe, C.H.; Jenney, A.; Mills, C.E.; Robitschek, E.J.; Davis, T.G.R.; Kim, S.; Fu, A.; Ma, X.; Gwee, J.; Tiwari, P.; Du, P.P.; Sindurakar, P.; Tian, J.; Mehta, A.; Schneider, A.M.; Yizhak, K.; Sade-Feldman, M.; LaSalle, T.; Sharova, T.; Xie, H.; Liu, S.; Michaud, W.A.; Saad-Beretta, R.; Yates, K.B.; Iracheta-Vellve, A.; Spetz, J.K.E.; Qin, X.; Sarosiek, K.A.; Zhang, G.; Kim, J.W.; Su, M.Y.; Cicerchia, A.M.; Rasmussen, M.Q.; Klempner, S.J.; Juric, D.; Pai, S.I.; Miller, D.M.; Giobbie-Hurder, A.; Chen, J.H.; Pelka, K.; Frederick, D.T.; Stinson, S.; Ivanova, E.; Aref, A.R.; Paweletz, C.P.; Barbie, D.A.; Sen, D.R.; Fisher, D.E.; Corcoran, R.B.; Hacohen, N.; Sorger, P.K.; Flaherty, K.T.; Boland, G.M.; Manguso, R.T.; Jenkins, R.W. Targeting TBK1 to overcome resistance to cancer immunotherapy. Nature, 2023, 615(7950), 158-167.
[http://dx.doi.org/10.1038/s41586-023-05704-6] [PMID: 36634707]
[67]
Cai, H.; Yan, L.; Liu, N.; Xu, M.; Cai, H. IFI16 promotes cervical cancer progression by upregulating PD-L1 in immunomicroenvironment through STING-TBK1-NF-kB pathway. Biomed. Pharmacother., 2020, 123, 109790.
[http://dx.doi.org/10.1016/j.biopha.2019.109790] [PMID: 31896065]
[68]
Jiang, Y.; Chen, S.; Li, Q.; Liang, J.; Lin, W.; Li, J.; Liu, Z.; Wen, M.; Cao, M.; Hong, J. TANK-binding kinase 1 (TBK1) serves as a potential target for hepatocellular carcinoma by enhancing tumor immune infiltration. Front. Immunol., 2021, 12, 612139.
[http://dx.doi.org/10.3389/fimmu.2021.612139] [PMID: 33679751]
[69]
Zhou, R.; Zhang, Q.; Xu, P. TBK1, a central kinase in innate immune sensing of nucleic acids and beyond. Acta Biochim. Biophys. Sin., 2020, 52(7), 757-767.
[http://dx.doi.org/10.1093/abbs/gmaa051] [PMID: 32458982]
[70]
Prabakaran, T.; Bodda, C.; Krapp, C.; Zhang, B.; Christensen, M.H.; Sun, C.; Reinert, L.; Cai, Y.; Jensen, S.B.; Skouboe, M.K.; Nyengaard, J.R.; Thompson, C.B.; Lebbink, R.J.; Sen, G.C.; van Loo, G.; Nielsen, R.; Komatsu, M.; Nejsum, L.N.; Jakobsen, M.R.; Gyrd-Hansen, M.; Paludan, S.R. Attenuation of c GAS ‐ STING signaling is mediated by a p62/SQSTM 1‐dependent autophagy pathway activated by TBK1. EMBO J., 2018, 37(8), e97858.
[http://dx.doi.org/10.15252/embj.201797858] [PMID: 29496741]
[71]
Pan, B.S.; Perera, S.A.; Piesvaux, J.A.; Presland, J.P.; Schroeder, G.K.; Cumming, J.N.; Trotter, B.W.; Altman, M.D.; Buevich, A.V.; Cash, B.; Cemerski, S.; Chang, W.; Chen, Y.; Dandliker, P.J.; Feng, G.; Haidle, A.; Henderson, T.; Jewell, J.; Kariv, I.; Knemeyer, I.; Kopinja, J.; Lacey, B.M.; Laskey, J.; Lesburg, C.A.; Liang, R.; Long, B.J.; Lu, M.; Ma, Y.; Minnihan, E.C.; O’Donnell, G.; Otte, R.; Price, L.; Rakhilina, L.; Sauvagnat, B.; Sharma, S.; Tyagarajan, S.; Woo, H.; Wyss, D.F.; Xu, S.; Bennett, D.J.; Addona, G.H. An orally available non-nucleotide STING agonist with antitumor activity. Science, 2020, 369(6506), eaba6098.
[http://dx.doi.org/10.1126/science.aba6098] [PMID: 32820094]
[72]
Zhang, H.; You, Q.D.; Xu, X.L. Targeting stimulator of interferon genes (STING): A medicinal chemistry perspective. J. Med. Chem., 2020, 63(8), 3785-3816.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01039] [PMID: 31820978]
[73]
Nandakumar, R.; Tschismarov, R.; Meissner, F.; Prabakaran, T.; Krissanaprasit, A.; Farahani, E.; Zhang, B.; Assil, S.; Martin, A.; Bertrams, W.; Holm, C.K.; Ablasser, A.; Klause, T.; Thomsen, M.K.; Schmeck, B.; Howard, K.A.; Henry, T.; Gothelf, K.V.; Decker, T.; Paludan, S.R. Intracellular bacteria engage a STING–TBK1–MVB12b pathway to enable paracrine cGAS–STING signalling. Nat. Microbiol., 2019, 4(4), 701-713.
[http://dx.doi.org/10.1038/s41564-019-0367-z] [PMID: 30804548]
[74]
Zhu, Z.H.; Aref, A.R.; Cohoon, T.J.; Barbie, T.U.; Imamura, Y.; Yang, S.H.; Moody, S.E.; Shen, R.R.; Schinzel, A.C.; Thai, T.C.; Reibel, J.B.; Tamayo, P.; Godfrey, J.T.; Qian, Z.R.; Page, A.N.; Maciag, K.; Chan, E.M.; Silkworth, W.; Labowsky, M.T.; Rozhansky, L.; Mesirov, J.P.; Gillanders, W.E.; Ogino, S.; Hacohen, N.; Gaudet, S.; Eck, M.J.; Engelman, J.A.; Corcoran, R.B.; Wong, K.K.; Hahn, W.C.; Barbie, D.A. Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov., 2014, 4(4), 452-465.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0646] [PMID: 24444711]
[75]
Cruz, V.H.; Arner, E.N.; Du, W.; Bremauntz, A.E.; Brekken, R.A. Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer. JCI Insight, 2019, 4(9), e126117.
[http://dx.doi.org/10.1172/jci.insight.126117] [PMID: 30938713]
[76]
Hu, L.; Xie, H.; Liu, X.; Potjewyd, F.; James, L.I.; Wilkerson, E.M.; Herring, L.E.; Xie, L.; Chen, X.; Cabrera, J.C.; Hong, K.; Liao, C.; Tan, X.; Baldwin, A.S.; Gong, K.; Zhang, Q. TBK1 Is a synthetic lethal target in cancer with VHL Loss. Cancer Discov., 2020, 10(3), 460-475.
[http://dx.doi.org/10.1158/2159-8290.CD-19-0837] [PMID: 31810986]
[77]
Basit, A.; Cho, M.G.; Kim, E.Y.; Kwon, D.; Kang, S.J.; Lee, J.H. The cGAS/STING/TBK1/IRF3 innate immunity pathway maintains chromosomal stability through regulation of p21 levels. Exp. Mol. Med., 2020, 52(4), 643-657.
[http://dx.doi.org/10.1038/s12276-020-0416-y] [PMID: 32284536]
[78]
Crew, A.P.; Raina, K.; Dong, H.; Qian, Y.; Wang, J.; Vigil, D.; Serebrenik, Y.V.; Hamman, B.D.; Morgan, A.; Ferraro, C.; Siu, K.; Neklesa, T.K.; Winkler, J.D.; Coleman, K.G.; Crews, C.M. Identification and characterization of Von hippel-lindau-recruiting proteolysis targeting chimeras (PROTACs) of TANK-binding kinase 1. J. Med. Chem., 2018, 61(2), 583-598.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00635] [PMID: 28692295]
[79]
Feldman, R.I.; Wu, J.M.; Polokoff, M.A.; Kochanny, M.J.; Dinter, H.; Zhu, D.; Biroc, S.L.; Alicke, B.; Bryant, J.; Yuan, S.; Buckman, B.O.; Lentz, D.; Ferrer, M.; Whitlow, M.; Adler, M.; Finster, S.; Chang, Z.; Arnaiz, D.O. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J. Biol. Chem., 2005, 280(20), 19867-19874.
[http://dx.doi.org/10.1074/jbc.M501367200] [PMID: 15772071]
[80]
Bai, L.Y.; Chiu, C.F.; Kapuriya, N.P.; Shieh, T.M.; Tsai, Y.C.; Wu, C.Y.; Sargeant, A.M.; Weng, J.R. BX795, a TBK1 inhibitor, exhibits antitumor activity in human oral squamous cell carcinoma through apoptosis induction and mitotic phase arrest. Eur. J. Pharmacol., 2015, 769, 287-296.
[http://dx.doi.org/10.1016/j.ejphar.2015.11.032] [PMID: 26607461]
[81]
Clark, K.; Peggie, M.; Plater, L.; Sorcek, R.J.; Young, E.R.R.; Madwed, J.B.; Hough, J.; McIver, E.G.; Cohen, P. Novel cross-talk within the IKK family controls innate immunity. Biochem. J., 2011, 434(1), 93-104.
[http://dx.doi.org/10.1042/BJ20101701] [PMID: 21138416]
[82]
McIver, E.G.; Bryans, J.; Birchall, K.; Chugh, J.; Drake, T.; Lewis, S.J.; Osborne, J.; Smiljanic-Hurley, E.; Tsang, W.; Kamal, A.; Levy, A.; Newman, M.; Taylor, D.; Arthur, J.S.C.; Clark, K.; Cohen, P. Synthesis and structure–activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases. Bioorg. Med. Chem. Lett., 2012, 22(23), 7169-7173.
[http://dx.doi.org/10.1016/j.bmcl.2012.09.063] [PMID: 23099093]
[83]
Li, J.; Huang, J.; Jeong, J.H.; Park, S.J.; Wei, R.; Peng, J.; Luo, Z.; Chen, Y.T.; Feng, Y.; Luo, J.L. Selective TBK1/IKKi dual inhibitors with anticancer potency. Int. J. Cancer, 2014, 134(8), 1972-1980.
[http://dx.doi.org/10.1002/ijc.28507] [PMID: 24150799]
[84]
Richters, A.; Basu, D.; Engel, J.; Ercanoglu, M.S.; Balke-Want, H.; Tesch, R.; Thomas, R.K.; Rauh, D. Identification and further development of potent TBK1 inhibitors. ACS Chem. Biol., 2015, 10(1), 289-298.
[http://dx.doi.org/10.1021/cb500908d] [PMID: 25540906]
[85]
Lee, S.J.; Gharbi, A.; You, J.S.; Han, H.D.; Kang, T.H.; Hong, S.H.; Park, W.S.; Jung, I.D.; Park, Y.M. Drug repositioning of TANK-binding kinase 1 inhibitor CYT387 as an alternative for the treatment of Gram-negative bacterial sepsis. Int. Immunopharmacol., 2019, 73, 482-490.
[http://dx.doi.org/10.1016/j.intimp.2019.05.051] [PMID: 31173970]
[86]
Thomson, D.W.; Poeckel, D.; Zinn, N.; Rau, C.; Strohmer, K.; Wagner, A.J.; Graves, A.P.; Perrin, J.; Bantscheff, M.; Duempelfeld, B.; Kasparcova, V.; Ramanjulu, J.M.; Pesiridis, G.S.; Muelbaier, M.; Bergamini, G. Discovery of GSK8612, a highly selective and potent TBK1 inhibitor. ACS Med. Chem. Lett., 2019, 10(5), 780-785.
[http://dx.doi.org/10.1021/acsmedchemlett.9b00027] [PMID: 31097999]
[87]
Beyett, T.S.; Gan, X.; Reilly, S.M.; Chang, L.; Gomez, A.V.; Saltiel, A.R.; Showalter, H.D.; Tesmer, J.J.G. Carboxylic acid derivatives of amlexanox display enhanced potency toward TBK1 and IKK ε and reveal mechanisms for selective inhibition. Mol. Pharmacol., 2018, 94(4), 1210-1219.
[http://dx.doi.org/10.1124/mol.118.112185] [PMID: 30082428]
[88]
Oral, E.A.; Reilly, S.M.; Gomez, A.V.; Meral, R.; Butz, L.; Ajluni, N.; Chenevert, T.L.; Korytnaya, E.; Neidert, A.H.; Hench, R.; Rus, D.; Horowitz, J.F.; Poirier, B.; Zhao, P.; Lehmann, K.; Jain, M.; Yu, R.; Liddle, C.; Ahmadian, M.; Downes, M.; Evans, R.M.; Saltiel, A.R. Inhibition of IKKɛ and TBK1 improves glucose control in a subset of patients with type 2 diabetes. Cell Metab., 2017, 26(1), 157-170.e7.
[http://dx.doi.org/10.1016/j.cmet.2017.06.006] [PMID: 28683283]
[89]
Lefranc, J.; Schulze, V.K.; Hillig, R.C.; Briem, H.; Prinz, F.; Mengel, A.; Heinrich, T.; Balint, J.; Rengachari, S.; Irlbacher, H.; Stöckigt, D.; Bömer, U.; Bader, B.; Gradl, S.N.; Nising, C.F.; von Nussbaum, F.; Mumberg, D.; Panne, D.; Wengner, A.M. Discovery of BAY-985, a highly selective TBK1/IKKε inhibitor. J. Med. Chem., 2020, 63(2), 601-612.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01460] [PMID: 31859507]
[90]
Sheridan, C. Drug developers switch gears to inhibit STING. Nat. Biotechnol., 2019, 37(3), 199-201.
[http://dx.doi.org/10.1038/s41587-019-0060-z] [PMID: 30833772]
[91]
Ng, K.W.; Marshall, E.A.; Bell, J.C.; Lam, W.L. cGAS–STING and Cancer: Dichotomous roles in tumor immunity and development. Trends Immunol., 2018, 39(1), 44-54.
[http://dx.doi.org/10.1016/j.it.2017.07.013] [PMID: 28830732]
[92]
Zhu, L.; Li, Y.; Xie, X.; Zhou, X.; Gu, M.; Jie, Z.; Ko, C.J.; Gao, T.; Hernandez, B.E.; Cheng, X.; Sun, S.C. TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis. Nat. Cell Biol., 2019, 21(12), 1604-1614.
[http://dx.doi.org/10.1038/s41556-019-0429-8] [PMID: 31792381]
[93]
Chen, D.S.; Mellman, I. Elements of cancer immunity and the cancer–immune set point. Nature, 2017, 541(7637), 321-330.
[http://dx.doi.org/10.1038/nature21349] [PMID: 28102259]
[94]
Balka, K.R.; Louis, C.; Saunders, T.L.; Smith, A.M.; Calleja, D.J.; D’Silva, D.B.; Moghaddas, F.; Tailler, M.; Lawlor, K.E.; Zhan, Y.; Burns, C.J.; Wicks, I.P.; Miner, J.J.; Kile, B.T.; Masters, S.L.; De Nardo, D. TBK1 and IKKε act redundantly to mediate sting-induced NF-κB responses in myeloid cells. Cell Rep., 2020, 31(1), 107492.
[http://dx.doi.org/10.1016/j.celrep.2020.03.056] [PMID: 32268090]
[95]
Cao, J.; Tong, C.; Liu, Y.; Wang, J.; Ni, X.; Xiong, M. Ginkgetin inhibits growth of breast carcinoma via regulating MAPKs pathway. Biomed. Pharmacother., 2017, 96, 450-458.
[http://dx.doi.org/10.1016/j.biopha.2017.09.077] [PMID: 29031204]
[96]
Rebecca, V.W.; Amaravadi, R.K. Emerging strategies to effectively target autophagy in cancer. Oncogene, 2016, 35(1), 1-11.
[http://dx.doi.org/10.1038/onc.2015.99] [PMID: 25893285]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy