|
|
TBK1的结构以及小分子抑制剂
|
Abstract:
坦克结合激酶1(Tank-Binding Kinase 1, TBK1)是天然免疫过程的重要调节因子，通过磷酸化干扰素调节因子3(Interferon Regurlartory Factor 3, IRF3)和干扰素调节因子7(Interferon Regurlartory Factor 7, IRF7)可诱导型干扰素和其他促炎细胞因子的产生。TBK1稳态的失调则会导致许多疾病如炎症、自身免疫性疾病、代谢性疾病和癌症的发展。因此，基于TBK1靶点开发新型高效抑制剂可进一步加深我们对于该靶点的认知，并确认其作为药物靶点的有效性。本文就TBK1蛋白结构以及一些有潜力的药物小分子进行综述。
Tank-Binding Kinase 1 (TBK1) is an important regulator of the natural immune process, inducing the production of interferon and other pro-inflammatory cytokines through phosphorylation of interferon regurlartory factor 3 (IRF3) and interferon regurlartory factor 7 (IRF7). Dysregulation of TBK1 homeostasis leads to the development of many diseases such as inflammatory/autoim- mune diseases, metabolic diseases and cancer. Therefore, the development of novel potent inhibitors based on the TBK1 target could further enhance our understanding of this target. Our knowledge of this target and its effectiveness as a drug target can be further enhanced. In this paper, we review the structure of TBK1 protein and some promising drug small molecules.
| [1] | Bowie, A.G. and Unterholzner, L. (2008) Viral Evasion and Subversion of Pattern-Recognition Receptor Signalling. Nature Reviews Immunology, 8, 911-922. https://doi.org/10.1038/nri2436 |
| [2] | Fitzgerald, K.A., McWhirter, S.M., Faia, K.L., Rowe, D.C., Latz, E., Golenbock, D.T., et al. (2003) IKKε and TBK1 Are Essential Components of the IRF3 Signaling Pathway. Nature Immunology, 4, 491-496.
https://doi.org/10.1038/ni921 |
| [3] | Abe, T., Barber, G.N. and Williams, B. (2014) Cytosolic-DNA-Mediated, STING-Dependent Proinflammatory Gene Induction Necessitates Canonical NF-κB Activation through TBK1. Journal of Virology, 88, 5328-5341.
https://doi.org/10.1128/JVI.00037-14 |
| [4] | Hammaker, D., Boyle, D.L. and Firestein, G.S. (2012) Synoviocyte Innate Immune Responses: TANK-Binding Kinase-1 as a Potential Therapeutic Target in Rheumatoid Arthritis. Rheumatology, 51, 610-618.
https://doi.org/10.1093/rheumatology/ker154 |
| [5] | Chau, T.-L., Gioia, R., Gatot, J.-S., Patrascu, F., Carpentier, I., Chapelle, J.-P., et al. (2008) Are the IKKs and IKK-Related Kinases TBK1 and IKK-？ Similarly Activated? Trends in Biochemical Sciences, 33, 171-180.
https://doi.org/10.1016/j.tibs.2008.01.002 |
| [6] | Wild, P., Farhan, H., McEwan, D.G., Wagner, S., Rogov, V.V., Brady, N.R., et al. (2011) Phosphorylation of the Autophagy Receptor Optineurin Restricts Salmonella Growth. Science, 333, 228-233.
https://doi.org/10.1126/science.1205405 |
| [7] | Hasan, M. and Yan, N. (2016) Therapeutic Potential of Targeting TBK1 in Autoimmune Diseases and Interferonopathies. Pharmacological Research, 111, 336-342. https://doi.org/10.1016/j.phrs.2016.04.008 |
| [8] | Reilly, S.M., Chiang, S.-H., Decker, S.J., Chang, L., Uhm, M., Larsen, M.J., et al. (2013) An Inhibitor of the Protein Kinases TBK1 and IKK-？ Improves Obesity-Related Metabolic Dysfunctions in Mice. Nature Medicine, 19, 313-321.
https://doi.org/10.1038/nm.3082 |
| [9] | Oral, E.A., Reilly, S.M., Gomez, A.V., Meral, R., Butz, L., Ajluni, N., et al. (2017) Inhibition of IKK？, and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes. Cell Metabolism, 26, 157-70.e7.
https://doi.org/10.1016/j.cmet.2017.06.006 |
| [10] | Xiao, Y., Zou, Q., Xie, X., Liu, T., Li, H.S., Jie, Z., et al. (2017) The Kinase TBK1 Functions in Dendritic Cells to Regulate T Cell Homeostasis, Autoimmunity, and Antitumor Immunity. Journal of Experimental Medicine, 214, 1493-1507. https://doi.org/10.1084/jem.20161524 |
| [11] | Barbie, D.A., Tamayo, P., Boehm, J.S., Kim, S.Y., Moody, S.E., Dunn, I.F., et al. (2009) Systematic RNA Interference Reveals That Oncogenic KRAS-Driven Cancers Require TBK1. Nature, 462, 108-112.
https://doi.org/10.1038/nature08460 |
| [12] | Oakes, J.A., Davies, M.C. and Collins, M.O. (2017) TBK1: A New Player in ALS Linking Autophagy and Neuroinflammation. Molecular Brain, 10, Article No. 5. https://doi.org/10.1186/s13041-017-0287-x |
| [13] | Tu, D., Zhu, Z., Zhou, A.Y., Yun, C.-H., Lee, K.-E., Toms Angela, V., et al. (2013) Structure and Ubiquitination-Dependent Activation of TANK-Binding Kinase 1. Cell Reports, 3, 747-758.
https://doi.org/10.1016/j.celrep.2013.01.033 |
| [14] | Larabi, A., Devos, J.M., Ng, S.-L., Nanao, M.H., Round, A., Maniatis, T., et al. (2013) Crystal Structure and Mechanism of Activation of TANK-Binding Kinase 1. Cell Reports, 3, 734-746. https://doi.org/10.1016/j.celrep.2013.01.034 |
| [15] | Ma, X., Helgason, E., Phung, Q.T., Quan, C.L., Iyer, R.S., Lee, M.W., et al. (2012) Molecular Basis of Tank-Binding Kinase 1 Activation by Transautophosphorylation. Proceedings of the National Academy of Sciences, 109, 9378.
https://doi.org/10.1073/pnas.1121552109 |
| [16] | Zhao, B., Du, F., Xu, P., Shu, C., Sankaran, B., Bell, S.L., et al. (2019) A Conserved PLPLRT/SD Motif of STING Mediates the Recruitment and Activation of TBK1. Nature, 569, 718-722. https://doi.org/10.1038/s41586-019-1228-x |
| [17] | Li, J., Li, J., Miyahira, A., Sun, J., Liu, Y., Cheng, G., et al. (2012) Crystal Structure of the Ubiquitin-Like Domain of Human TBK1. Protein & Cell, 3, 383-391. https://doi.org/10.1007/s13238-012-2929-1 |
| [18] | Zhao, C. and Zhao, W. (2019) TANK-Binding Kinase 1 as a Novel Therapeutic Target for Viral Diseases. Expert Opinion on Therapeutic Targets, 23, 437-446. https://doi.org/10.1080/14728222.2019.1601702 |
| [19] | Zhang, T., Qian, Y., Wang, S., Huang, G., Zhang, L. and Xue, Z. (2019) Influence of the Heat Dissipation Mode of Long-Flute Cutting Tools on Temperature Distribution during HFCVD Diamond Films. Crystals, 9, 394.
https://doi.org/10.3390/cryst9080394 |
| [20] | Lei, C.-Q., Zhong, B., Zhang, Y., Zhang, J., Wang, S. and Shu, H.-B. (2010) Glycogen Synthase Kinase 3β Regulates IRF3 Transcription Factor-Mediated Antiviral Response via Activation of the Kinase TBK1. Immunity, 33, 878-889.
https://doi.org/10.1016/j.immuni.2010.11.021 |
| [21] | Zhao, P., Wong, K.I., Sun, X., Reilly, S.M., Uhm, M., Liao, Z., et al. (2018) TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue. Cell, 172, 731-43.e12. https://doi.org/10.1016/j.cell.2018.01.007 |
| [22] | Lama, L., Adura, C., Xie, W., Tomita, D., Kamei, T., Kuryavyi, V., et al. (2019) Development of Human cGAS-Specific Small-Molecule Inhibitors for Repression of dsDNA-Triggered Interferon Expression. Nature Communications, 10, 2261. https://doi.org/10.1038/s41467-019-08620-4 |
| [23] | Bai, L.-Y., Chiu, C.-F., Kapuriya, N.P., Shieh, T.-M., Tsai, Y.-C., Wu, C.-Y., et al. (2015) BX795, a TBK1 Inhibitor, Exhibits Antitumor Activity in Human Oral Squamous Cell Carcinoma through Apoptosis Induction and Mitotic Phase Arrest. European Journal of Pharmacology, 769, 287-296. https://doi.org/10.1016/j.ejphar.2015.11.032 |
| [24] | Chen, W., Luo, K., Ke, Z., Kuai, B., He, S., Jiang, W., et al. (2017) TBK1 Promote Bladder Cancer Cell Proliferation and Migration via Akt Signaling. Journal of Cancer, 8, 1892-1899. https://doi.org/10.7150/jca.17638 |
| [25] | Choi, E.A., Choi, Y.-S., Lee, E.J., Singh, S.R., Kim, S.C. and Chang, S. (2019) A Pharmacogenomic Analysis Using L1000CDS2 Identifies BX-795 as a Potential Anticancer Drug for Primary Pancreatic Ductal Adenocarcinoma Cells. Cancer Letters, 465, 82-93. https://doi.org/10.1016/j.canlet.2019.08.002 |
| [26] | Clark, K., Peggie, M., Plater, L., Sorcek, R.J., Young, E.R.R., Madwed, J.B., et al. (2011) Novel Cross-Talk within the IKK Family Controls Innate Immunity. Biochemical Journal, 434, 93-104. https://doi.org/10.1042/BJ20101701 |
| [27] | Pardanani, A., Lasho, T., Smith, G., Burns, C.J., Fantino, E. and Tefferi, A. (2009) CYT387, a Selective JAK1/JAK2 Inhibitor: In Vitro Assessment of Kinase Selectivity and Preclinical Studies Using Cell Lines and Primary Cells from Polycythemia Vera Patients. Leukemia, 23, 1441-1445. https://doi.org/10.1038/leu.2009.50 |
| [28] | Ng, A.H.S. (2018) Nationalism and the Intangible Effects of Violence in Malik Sajad’s Munnu: A Boy from Kashmir. South Asian Review, 39, 159-174. https://doi.org/10.1080/02759527.2018.1515803 |
| [29] | Thomson, D.W., Poeckel, D., Zinn, N., Rau, C., Strohmer, K., Wagner, A.J., et al. (2019) Discovery of GSK8612, a Highly Selective and Potent TBK1 Inhibitor. ACS Medicinal Chemistry Letters, 10, 780-785.
https://doi.org/10.1021/acsmedchemlett.9b00027 |
| [30] | Beyett, T.S., Gan, X., Reilly, S.M., Chang, L., Gomez, A.V., Saltiel, A.R., et al. (2018) Carboxylic Acid Derivatives of Amlexanox Display Enhanced Potency toward TBK1 and IKK ？ and Reveal Mechanisms for Selective Inhibition. Molecular Pharmacology, 94, 1210-1219. https://doi.org/10.1124/mol.118.112185 |
| [31] | Zhou, Z., Qi, J., Zhao, J., Lim, C.W., Kim, J.-W. and Kim, B. (2020) Dual TBK1/IKK？ Inhibitor Amlexanox Attenuates the Severity of Hepatotoxin-Induced Liver Fibrosis and Biliary Fibrosis in Mice. Journal of Cellular and Molecular Medicine, 24, 1383-1398. https://doi.org/10.1111/jcmm.14817 |
| [32] | Maniaci, C. and Ciulli, A. (2019) Bifunctional Chemical Probes Inducing Protein-Protein Interactions. Current Opinion in Chemical Biology, 52, 145-156. https://doi.org/10.1016/j.cbpa.2019.07.003 |
| [33] | Crew, A.P., Raina, K., Dong, H., Qian, Y., Wang, J., Vigil, D., et al. (2018) Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1. Journal of Medicinal Chemistry, 61, 583-598. https://doi.org/10.1021/acs.jmedchem.7b00635 |
| [34] | Johannes, J.W., Chuaqui, C., Cowen, S., Devereaux, E., Gingipalli, L., Molina, A., et al. (2014) Discovery of 6-aryl-azabenzimidaoles That Inhibit the TBK1/IKK-ε Kinases. Bioorganic & Medicinal Chemistry Letters, 24, 1138-1143. https://doi.org/10.1016/j.bmcl.2013.12.123 |
| [35] | Wang, T., Block, M.A., Cowen, S., Davies, A.M., Devereaux, E., Gingipalli, L., et al. (2012) Discovery of Azabenzimidazole Derivatives as Potent, Selective Inhibitors of TBK1/IKK Kinases. Bioorganic and Medicinal Chemistry Letters, 22, 2063-2069. https://doi.org/10.1016/j.bmcl.2012.01.018 |
| [36] | Vu, H.L. and Aplin, A.E. (2014) Targeting TBK1 Inhibits Migration and Resistance to MEK Inhibitors in Mutant NRAS Melanoma. Molecular Cancer Research, 12, 1509-1519. https://doi.org/10.1158/1541-7786.MCR-14-0204 |
| [37] | Hasan, M., Dobbs, N., Khan, S., White, M.A., Wakeland, E.K., Li, Q.-Z., et al. (2015) Cutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice. The Journal of Immunology, 195, 4573-4577.
https://doi.org/10.4049/jimmunol.1500162 |
