BTK抑制剂治疗炎症和自身免疫性疾病的研究进展
Research Progress of BTK Inhibitors in the Treatment of Inflammatory and Autoimmune Diseases
摘要: 布鲁顿酪氨酸激酶(BTK)在B细胞受体和Fc受体信号通路具有至关重要的作用，同时还参与Toll样受体和趋化因子受体的调节，由于其在免疫过程中的核心作用，BTK抑制作为一种治疗炎症和自身免疫性疾病的方法具有巨大潜力。现已上市了五款BTK抑制剂，其适应症主要集中在抗肿瘤领域。本文综述了BTK的结构功能以及近五年在治疗炎症和自身免疫性疾病领域内BTK小分子抑制剂的研究进展，以求为此领域的进一步研究工作提供理论帮助和指导。
Abstract: Bruton’s tyrosine kinase (BTK) plays a crucial role in B-cell receptor and Fc receptor signaling pathways. BTK is also involved in the regulation of Toll-like receptors and chemokine receptors. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic ap-proach for the treatment of inflammatory and autoimmune diseases. Five BTK inhibitors have been listed, and their indications are mainly in the field of anti-tumor. This article reviewed the structure and function of BTK and the research progress of BTK inhibitors in the treatment of inflammation and autoimmune diseases in the past five years, which provided theoretical help and guidance for further research in the field.
文章引用：杨婉萍, 房小宝, 马宇乐, 施志浩. BTK抑制剂治疗炎症和自身免疫性疾病的研究进展[J]. 药物化学, 2022, 10(1): 70-83. https://doi.org/10.12677/HJMCe.2022.101008

参考文献

[1] Smith, C.I.E., Backesjo, C.M., Berglof, A., et al. (1998) X-Linked Agammaglobulinemia: Lack of Mature B Lineage Cells Caused by Mutations in the Btk Kinase. Springer Seminars in Immunopathology, 19, 369-381. [Google Scholar] [CrossRef] 
[2] Mohamed, A.J., Yu, L., Backesjo, C.M., et al. (2009) Bruton’s Tyro-sine Kinase (Btk): Function, Regulation, and Transformation with Special Emphasis on the PH Domain. Immunological Reviews, 228, 58-73. [Google Scholar] [CrossRef] 
[3] Fasano, S. and Isenberg, D.A. (2019) Present and Novel Biologic Drugs in Primary Sjögren’s Syndrome. Clinical and Experimental Rheumatology, 37, S167-S174.
[4] Kinnunen, T., Chamberlain, N., Morbach, H., et al. (2013) Specific Peripheral B Cell Tolerance De-fects in Patients with Multiple Sclerosis. Journal of Clinical Investigation, 123, 2737-2741.
[5] Di Paolo, J.A., Huang, T., Balazs, M., et al. (2011) Specific Btk Inhibition Suppresses B Cell- and Myeloid Cell-Mediated Arthritis. Nature Chemical Biology, 7, 41-50. [Google Scholar] [CrossRef] [PubMed]
[6] Roschewski, M., Lionakis, M.S., Sharman, J.P., et al. (2020) Inhibition of Bruton Tyrosine Kinase in Patients with Severe COVID-19. Science Immunology, 5, eabd0110. [Google Scholar] [CrossRef] [PubMed]
[7] Akinleye, A., Chen, Y., Mukhi, N., et al. (2013) Ib-rutinib and Novel BTK Inhibitors in Clinical Development. Journal of Hematology & Oncology, 6, Article No. 59. [Google Scholar] [CrossRef] [PubMed]
[8] Burger, J.A. and Wiestner, A. (2018) Targeting B Cell Receptor Signalling in Cancer: Preclinical and Clinical Advances. Nature Reviews Cancer, 18, 148-167. [Google Scholar] [CrossRef] [PubMed]
[9] Nimmerjahn, F. and Ravetch, J.V. (2008) Fcγ Receptors as Regulators of Immune Responses. Nature Reviews Immunology, 8, 34-47.
[10] Hata, D., Kawakami, Y., Inagaki, N., et al. (1998) Involvement of Bruton’s Tyrosine Kinase in FcεRI-Dependent Mast Cell Degranulation and Cytokine Production. Jour-nal of Experimental Medicine, 187, 1235-1247. [Google Scholar] [CrossRef] [PubMed]
[11] Smiljkovic, D., Blatt, K., Stefanzl, G., et al. (2017) BTK Inhibition Is a Potent Approach to Block IgE-Mediated Histamine Release in Human Basophils. Allergy, 72, 1666-1676. [Google Scholar] [CrossRef] [PubMed]
[12] Takeuchi, O. and Akira, S. (2010) Pattern Recognition Receptors and In-flammation. Cell, 140, 805-820. [Google Scholar] [CrossRef] [PubMed]
[13] Rawlings, D.J., Schwartz, M.A., Jackson, S.W., et al. (2012) Inte-gration of B Cell Responses through Toll-Like Receptors and Antigen Receptors. Nature Reviews Immunology, 12, 282-294. [Google Scholar] [CrossRef] [PubMed]
[14] Katewa, A., Wang, Y.G., Hackney, J.A., et al. (2017) Btk-Specific Inhibition Blocks Pathogenic Plasma Cell Signatures and Myeloid Cell-Associated Damage in IFNα-Driven Lupus Ne-phritis. JCI Insight, 2, e90111.
[15] Liclican, A., Serafini, L., Xing, W., et al. (2020) Biochemical Characterization of Tirabrutinib and Other Irreversible Inhibitors of Bruton’s Tyrosine Kinase Reveals Differences in On- and Off-Target In-hibition. Biochimica et Biophysica Acta (BBA)—General Subjects, 1864, Article ID: 129531. [Google Scholar] [CrossRef] [PubMed]
[16] Owens, T. (2018) Discovery of PRN1008: A Reversible Co-valent BTK Inhibitor for Treatment of Autoimmune Diseases. Proceedings of the 255th American Chemical Society Na-tional Meeting & Exposition, New Orleans, 18-22 March 2018.
[17] Smith, P.F., Krishnarajah, J., Nunn, P.A., et al. (2017) A Phase I Trial of PRN1008, a Novel Reversible Covalent Inhibitor of Bruton’s Tyrosine Kinase, in Healthy Volunteers. British Journal of Clinical Pharmacology, 83, 2367-2376. [Google Scholar] [CrossRef] [PubMed]
[18] Barf, T., Covey, T., Izumi, R., et al. (2017) Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and in Vivo Potency Profile. Journal of Pharmacology and Experimental Therapeutics, 363, 240-252. [Google Scholar] [CrossRef] [PubMed]
[19] Treon, S.P., Tripsas, C.K., Meid, K., et al. (2015) Ibrutinib in Previously Treated Waldenstrm’s Macroglobulinemia. New Eng-land Journal of Medicine, 372, 1430-1440. [Google Scholar] [CrossRef] 
[20] Yoshizawa, T., Ariza, Y., Ueda, Y., et al. (2012) Development of a Bruton’s Tyrosine Kinase (BTK) Inhibitor, ONO-4059: Efficacy in a Col-lagen Induced Arthritis (CIA) Model Indicates Potential Treatment for Rheumatoid Arthritis (RA). Arthritis and Rheu-matism, 64, S709-S.
[21] Burger, J.A. (2014) Bruton’s Tyrosine Kinase (BTK) Inhibitors in Clinical Trials. Current Hematologic Malignancy Reports, 9, 44-49. [Google Scholar] [CrossRef] [PubMed]
[22] Dhillon, S. (2020) Tirabrutinib: First Approval. Drugs, 80, 835-840. [Google Scholar] [CrossRef] [PubMed]
[23] Zhang, B., Zhao, R.B., Liang, R.X., et al. (2020) Abstract CT132: Orelabrutinib, a Potent and Selective Bruton’s Tyrosine Kinase Inhibitor with Superior Safety Profile and Excellent PK/PD Properties. Proceedings of the AACR Annual Meeting 2020, Philadelphia, PA, 27-28 April 2020 and 22-24 June 2020. [Google Scholar] [CrossRef] 
[24] Dahl, K., Turner, T. and Vasdev, N. (2020) Radiosyn-thesis of a Bruton’s Tyrosine Kinase Inhibitor, [11C]Tolebrutinib, via Palladium-NiXantphos-Mediated Carbonylation. Journal of Labelled Compounds and Radiopharmaceuticals, 63, 482-487. [Google Scholar] [CrossRef] [PubMed]
[25] Zhao, D., Huang, S.S., Qu, M.H., et al. (2017) Structural Optimization of Diphenylpyrimidine Derivatives (DPPYs) as Potent Bruton’s Tyrosine Kinase (BTK) Inhibitors with Improved Activity toward B Leukemia Cell Lines. European Journal of Medicinal Chemistry, 126, 444-455. [Google Scholar] [CrossRef] [PubMed]
[26] Evans, E.K., Tester, R., Aslanian, S., et al. (2013) Inhibition of Btk with CC-292 Provides Early Pharmacodynamic Assessment of Activity in Mice and Humans. Journal of Pharma-cology and Experimental Therapeutics, 346, 219-228. [Google Scholar] [CrossRef] [PubMed]
[27] Caldwell, R.D., Qiu, H., Askew, B.C., et al. (2019) Discovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton’s Tyrosine Kinase (BTK) Inhibitor for the Treat-ment of Immunological Diseases. Journal of Medicinal Chemistry, 62, 7643-7655. [Google Scholar] [CrossRef] [PubMed]
[28] Angst, D., Gessier, F., Janser, P., et al. (2020) Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase. Journal of Me-dicinal Chemistry, 63, 5102-5118. [Google Scholar] [CrossRef] [PubMed]
[29] Liu, Q., Batt, D.G., Chaudhry, C., et al. (2018) Conversion of Carbazole Carboxamide Based Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK) into Potent, Selective Irreversi-ble Inhibitors in the Carbazole, Tetrahydrocarbazole, and a New 2,3-Dimethylindole Series. Bioorganic & Medicinal Chemistry Letters, 28, 3080-3084. [Google Scholar] [CrossRef] [PubMed]
[30] Watterson, S.H., Liu, Q., Bertrand, M.B., et al. (2019) Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton’s Tyrosine Kinase (BTK). Journal of Medicinal Chemistry, 62, 3228-3250. [Google Scholar] [CrossRef] [PubMed]
[31] Young, W.B., Barbosa, J., Blomgren, P., et al. (2015) Potent and Selective Bruton’s Tyrosine Kinase Inhibitors: Discovery of GDC-0834. Bioorganic & Medicinal Chemistry Letters, 25, 1333-1337. [Google Scholar] [CrossRef] [PubMed]
[32] Hopkins, B.T., Bame, E., Bajrami, B., et al. (2021) Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis. Journal of Medicinal Chemistry, 65, 1206-1224.
[33] Liu, J., Guiadeen, D., Krikorian, A., et al. (2020) Potent, Non-Covalent Reversible BTK Inhibitors with 8-Amino- Imidazo[1,5-a] Pyrazine Core Featuring 3-Position Bicyclic Ring Substitutes. Bioorganic & Medicinal Chemistry Letters, 30, Article ID: 127390. [Google Scholar] [CrossRef] [PubMed]
[34] Smith, C.R., Dougan, D.R., Komandla, M., et al. (2015) Frag-ment-Based Discovery of a Small Molecule Inhibitor of Bruton’s Tyrosine Kinase. Journal of Medicinal Chemistry, 58, 5437-5444. [Google Scholar] [CrossRef] [PubMed]
[35] Yao, X., Sun, X.Y., Jin, S.Y., et al. (2019) Discovery of 4-Aminoquinoline-3-Carboxamide Derivatives as Potent Reversible Bruton’s Tyrosine Kinase Inhibitors for the Treat-ment of Rheumatoid Arthritis. Journal of Medicinal Chemistry, 62, 6561-6574. [Google Scholar] [CrossRef] [PubMed]
[36] Wang, X.J., Barbosa, J., Blomgren, P., et al. (2017) Discov-ery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties. ACS Medicinal Chemistry Letters, 8, 608-613. [Google Scholar] [CrossRef] [PubMed]
[37] Crawford, J.J.Y., Johnson, A.R., Misner, D.L., et al. (2018) Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton’s Tyrosine Kinase Inhibitor in Early Clinical De-velopment. Journal of Medicinal Chemistry, 61, 2227- 2245. [Google Scholar] [CrossRef] [PubMed]
[38] Cohen, S., Tuckwell, K., Katsumoto, T.R., et al. (2020) Fenebrutinib versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double-Blind, Phase II Trial. Ar-thritis & Rheumatology, 72, 1435-1446. [Google Scholar] [CrossRef] [PubMed]
[39] Zhang, D.T., Gong, H. and Meng, F.C. (2021) Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases. Molecules, 26, Article No. 4907. [Google Scholar] [CrossRef] [PubMed]