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PD-1/PD-L1小分子抑制剂临床进展
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Abstract:
PD-1/PD-L1是维持机体稳态的免疫检查点共抑制分子，与肿瘤免疫逃逸密切相关。目前全球已有22款PD-1/PD-L1单抗获批用于治疗各类恶性肿瘤，然而小分子抑制剂的研发却进展缓慢。自2015年百时美施贵宝公司公开第一份联苯类化合物专利以来，至今已有15款PD-1/PD-L1小分子抑制剂进入临床开发。本文从简介PD-1/PD-L1的结构和信号通路出发，分析部分PD-1/PD-L1小分子抑制剂的临床前研究，侧重综述该类小分子抑制剂临床研究的进展。
PD-1/PD-L1 is an immune checkpoint co-suppressor molecule that maintains homeostasis in the body and is closely related to tumor immune escape. At present, 22 types of PD-1/PD-L1 monoclonal antibody have been approved globally for the treatment of various therioma, while the development of small molecule inhibitors is progressing slowly. Since the disclosure of the first patent for biphenyl compounds by Bristol Myers Squibb Company in 2015, 15 types of PD-1/PD-L1 small molecule inhibitor have been developed in clinical trials to date. This article starts with an introduction to the structure and signaling pathways of PD-1/PD-L1, analyzes the preclinical studies of some small molecule inhibitors of PD-1/PD-L1, and focuses on reviewing the progress of clinical research on this type of small molecule inhibitor.
| [1] | Sharma, P., Goswami, S., Raychaudhuri, D., et al. (2023) Immune Checkpoint Therapy—Current Perspectives and Future Directions. Cell, 186, 1652-1669. https://doi.org/10.1016/j.cell.2023.03.006 |
| [2] | Weiss, S.A. and Kluger, H. (2021) CheckMate-067: Raising the Bar for the Next Decade in Oncology. Journal of Clinical Oncology, 40, 111-113. https://doi.org/10.1200/JCO.21.02549 |
| [3] | Robert, C., Carlino, M.S., McNeil, C., et al. (2023) Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab versus Ipilimumab in Advanced Melanoma. Journal of Clinical Oncology, 41, 3998-4003. https://doi.org/10.1200/JCO.22.01599 |
| [4] | Merck公司2023年财报[EB/OL]. https://www.merck.com/news/merck-announces-fourth-quarter-and-full-year-2023-financial-results/, 2024-03-22. |
| [5] | Romero, Y., Wise, R. and Zolkiewska, A. (2020) Proteolytic Processing of PD-L1 by ADAM Proteases in Breast Cancer Cells. Cancer Immunology, Immunotherapy, 69, 43-55. https://doi.org/10.1007/s00262-019-02437-2 |
| [6] | Patsoukis, N., Wang, Q., Strauss, L., et al. (2020) Revisiting the PD-1 Pathway. Science Advances, 6, Article eabd2712. https://doi.org/10.1126/sciadv.abd2712 |
| [7] | Yokosuka, T., Takamatsu, M., Kobayashi-Imanishi, W., et al. (2012) Programmed Cell Death 1 Forms Negative Costimulatory Microclusters that Directly Inhibit T Cell Receptor Signaling by Recruiting Phosphatase SHP2. Journal of Experimental Medicine, 209, 1201-1217. https://doi.org/10.1084/jem.20112741 |
| [8] | Chen, Y., Liu, P., Gao, F., et al. (2010) A Dimeric Structure of PD-L1: Functional Units or Evolutionary Relics? Protein & Cell, 1, 153-160. https://doi.org/10.1007/s13238-010-0022-1 |
| [9] | Hira-Miyazawa, M., Nakamura, H., Hirai, M., et al. (2018) Regulation of Programmed-Death Ligand in the Human Head and Neck Squamous Cell Carcinoma Microenvironment Is Mediated through Matrix Metalloproteinase-Mediated Proteolytic Cleavage. International Journal of Oncology, 52, 379-388. https://doi.org/10.3892/ijo.2017.4221 |
| [10] | Kathleen, M.M., Petra, R.-M., Long, Y., et al. (2022) Soluble PD-L1 as an Early Marker of Progressive Disease on Nivolumab. Journal for ImmunoTherapy of Cancer, 10, Article e003527. https://doi.org/10.1136/jitc-2021-003527 |
| [11] | Yin, Z., Yu, M., Ma, T., et al. (2021) Mechanisms Underlying Low-Clinical Responses to PD-1/PD-L1 Blocking Antibodies in Immunotherapy of Cancer: A Key Role of Exosomal PD-L1. Journal for ImmunoTherapy of Cancer, 9, Article e001698. https://doi.org/10.1136/jitc-2020-001698 |
| [12] | Nagato, T., Ohkuri, T., Ohara, K., et al. (2017) Programmed Death-Ligand 1 and Its Soluble Form Are Highly Expressed in Nasal Natural Killer/T-Cell Lymphoma: A Potential Rationale for Immunotherapy. Cancer Immunology, Immunotherapy, 66, 877-890. https://doi.org/10.1007/s00262-017-1987-x |
| [13] | Bardhan, K., Aksoylar, H.-I., Le Bourgeois, T., et al. (2020) Publisher Correction: Phosphorylation of PD-1-Y248 Is a Marker of PD-1-Mediated Inhibitory Function in Human T Cells. Scientific Reports, 10, Article No. 15905. https://doi.org/10.1038/s41598-020-71090-y |
| [14] | Saunders, P.A., Hendrycks, V.R., Lidinsky, W.A., et al. (2005) PD-L2: PD-1 Involvement in T Cell Proliferation, Cytokine Production, and Integrin-Mediated Adhesion. European Journal of Immunology, 35, 3561-3569. https://doi.org/10.1002/eji.200526347 |
| [15] | Jiang, M., Liu, M., Liu, G., et al. (2023) Advances in the Structural Characterization of Complexes of Therapeutic Antibodies with PD-1 or PD-L1. mAbs, 15, Article 2236740. https://doi.org/10.1080/19420862.2023.2236740 |
| [16] | Zak, K.M., Grudnik, P., Guzik, K., et al. (2016) Structural Basis for Small Molecule Targeting of the Programmed Death Ligand 1 (PD-L1). Oncotarget, 7, 30323-30335. https://doi.org/10.18632/oncotarget.8730 |
| [17] | Guo, J., Yu, F., Zhang, K., et al. (2024) Beyond Inhibition against the PD-1/PD-L1 Pathway: Development of PD-L1 Inhibitors Targeting Internalization and Degradation of PD-L1. RSC Medicinal Chemistry. https://doi.org/10.1039/D3MD00636K |
| [18] | Muszak, D., Surmiak, E., Plewka, J., et al. (2021) Terphenyl-Based Small-Molecule Inhibitors of Programmed Cell Death-1/Programmed Death-Ligand 1 Protein—Protein Interaction. Journal of Medicinal Chemistry, 64, 11614-11636. https://doi.org/10.1021/acs.jmedchem.1c00957 |
| [19] | Zheng, X. and Chupak, L.S. (2015) Compounds Useful as Immunomodulators. WO Patent No. 2015034820A1. |
| [20] | Ding, M., Hewawasam, P., Langley, D.R., et al. (2015) Compounds Useful as Immunomodulators. WO Patent No. 2015160641A2. |
| [21] | Hewawasam, P., Langley, D.R., Yeung, K.-S., et al. (2017) Compounds Useful as Immunomodulators. WO Patent No. 2017066227A1. |
| [22] | Wu, L.X., Li, J.W., Qi, C., et al. (2018) Benzooxazole Derivatives as Immunomodulators. WO Patent No. 2018-119266A1. |
| [23] | 冯志强, 陈晓光, 杨阳, 等. 烟醇醚类衍生物、及其制法和药物组合物与用途[P]. 中国专利, 114853634A. 2022-08-05. |
| [24] | Cho, A., Graupe, M., Xu, J., et al. (2019) Pd-1/Pd-L1 Inhibitors. WO Patent No. 2018195321A1. |
| [25] | 王玉光, 张农, 吴添智, 等. 芳香乙烯或芳香乙基类衍生物、其制备方法、中间体、药物组合物及应用[P]. 中国专利, 109988144A. 2019-07-09. |
| [26] | Sarina, P.-P., Tara, M., Solmaz, S., et al. (2020) 419 Pharmacodynamic Biomarkers Demonstrate T-Cell Activation in Patients Treated with the Oral PD-L1 Inhibitor INCB086550 in a Phase 1 Clinical Trial. Journal for ImmunoTherapy of Cancer, 8, A255. |
| [27] | Eric Van, C., Hans, P., Brant, D., et al. (2021) 529 Phase 1 Study of INCB086550, an Oral PD-L1 Inhibitor, in Immune-Checkpoint Naive Patients with Advanced Solid Tumors. Journal for ImmunoTherapy of Cancer, 9, A559. https://doi.org/10.1136/jitc-2021-SITC2021.529 |
| [28] | Pinato, D.J., Banerji, U., Rottey, S., et al. (2023) 134P A Phase I Study Exploring the Safety and Tolerability of the All Molecule PD-L1 Inhibitor INCB099318 in Select Advanced Solid Tumors. Immuno-Oncology Technology, 20, Article 100606. https://doi.org/10.1016/j.iotech.2023.100606 |
| [29] | 美国临床试验数据库[EB/OL]. https://clinicaltrials.gov/, 2024-02-24. |
| [30] | Hans, P., Thierry, L., Marie, R., et al. (2022) 734 A Phase 1 Study Exploring the Safety and Tolerability of the Small-Molecule PD-L1 Inhibitor, INCB099280, in Patients with Select Advanced Solid Tumors. Journal for ImmunoTherapy of Cancer, 10, A766. |
| [31] | David, P., Ruth, P., Martin, G., et al. (2022) 622 A Phase 1 Study Exploring the Safety and Tolerability of the Small-Molecule PD-L1 Inhibitor, INCB099318, in Patients with Select Advanced Solid Tumors. Journal for ImmunoTherapy of Cancer, 10, A654. |
| [32] | Lai, F., Ji, M., Huang, L., et al. (2022) YPD-30, a Prodrug of YPD-29B, Is an Oral Small-Molecule Inhibitor Targeting PD-L1 for the Treatment of Human Cancer. Acta Pharmaceutica Sinica B, 12, 2845-2858. https://doi.org/10.1016/j.apsb.2022.02.031 |
| [33] | Jiang, J., Zou, X., Liu, Y., et al. (2021) Simultaneous Determination of a Novel PD-L1 Inhibitor, IMMH-010, and Its Active Metabolite, YPD-29B, in Rat Biological Matrices by Polarity-Switching Liquid Chromatography-Tandem Mass Spectrometry: Application to ADME Studies. Frontiers in Pharmacology, 12, Article 677120. https://doi.org/10.3389/fphar.2021.677120 |
| [34] | Wang, Y., Liu, X., Zou, X., et al. (2021) Metabolism and Interspecies Variation of IMMH-010, a Programmed Cell Death Ligand 1 Inhibitor Prodrug. Pharmaceutics, 13, Article 598. https://doi.org/10.3390/pharmaceutics13050598 |
| [35] | 再极医药[EB/OL]. http://www.maxinovel.com/news.html, 2024-02-24. |
| [36] | 贝达药业[EB/OL]. https://www.bettapharma.com/newdrug/projects, 2024-03-16. |
| [37] | 王义乾, 张垚, 张春辉, 等. 免疫调节剂及其组合物和应用[P]. 中国专利, 115884972A. 2023-03-31. |
| [38] | 阿诺生物医药[EB/OL]. https://cn.adlainortye.com/index.php/newsinfo?id=81, 2024-03-15. |
| [39] | Yu, Z.Y., Li, P., Xu, B.D., et al. (2021) PD-1/PD-L1 Inhibitors. WO Patent No. 2021129584A1. |
| [40] | Liu, L., Yao, Z., Wang, S., et al. (2021) Syntheses, Biological Evaluations, and Mechanistic Studies of Benzo[c][1,2,5] Oxadiazole Derivatives as Potent PD-L1 Inhibitors with in vivo Antitumor Activity. Journal of Medicinal Chemistry, 64, 8391-8409. https://doi.org/10.1021/acs.jmedchem.1c00392 |
| [41] | Wang, T., Cai, S., Wang, M., et al. (2021) Novel Biphenyl Pyridines as Potent Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction. Journal of Medicinal Chemistry, 64, 7390-7403. https://doi.org/10.1021/acs.jmedchem.1c00010 |
| [42] | 孙宏斌, 刘鎏, 王仕军, 等. 联苯类化合物及其制备方法和医药用途[P]. 中国专利, 111909108A. 2020-11-10. |
| [43] | 蒋晟, 郝海平, 王天雨, 等. 苯基取代的五元杂环类化合物及其制备方法、用途和药物组合物[P]. 中国专利, 111718310A. 2020-09-29. |
| [44] | 徐云根, 张宏波, 朱启华, 等. 一种新型联苯类衍生物及其制备方法与医药用途[P]. 中国专利, 113135895A. 2021-07-20. |
| [45] | 徐云根, 张宏波, 朱启华, 等. 一种新型联苯类衍生物及其制备方法与医药用途[P]. 中国专利, 113461668A. 2021-10-01. |
| [46] | Guo, Y., Jin, Y., Wang, B., et al. (2021) Molecular Mechanism of Small-Molecule Inhibitors in Blocking the PD-1/ PD-L1 Pathway through PD-L1 Dimerization. International Journal of Molecular Sciences, 22, Article 4766. https://doi.org/10.3390/ijms22094766 |
