|
|
EGFR变构抑制剂在小细胞肺癌治疗中的作用和未来发展
|
Abstract:
表皮生长因子受体(EGFR)过表达和突变与非小细胞肺癌的发生密切相关。EGFR激活突变作为非小细胞肺癌的致癌因素，EGFR小分子抑制剂的开发也不断在进行。然而从2016年首次报道EGFRC797S突变成为第三代不可逆抑制剂的主要耐药机制以来，至今仍未有对抗EGFRC797S三级突变特效药获得审批。因此，开发第四代EGFR抑制剂具有重要意义。本文综述了EGFR继发性突变的过程以及EGFR变构抑制剂的最新药物化学进展。我们希望这些数据能启发读者新的想法，开发出对EGFRC797S突变有效的新型第四代EGFR变构抑制剂。
Epidermal growth factor receptor (EGFR) overexpression and mutations are closely associated with the development of non-small cell lung cancer. EGFR-activating mutations function as oncogenic drivers in non-small cell lung cancer, driving ongoing efforts in the development of small-molecule inhibitors targeting EGFR. However, since the identification of the EGFRC797S mutation in 2016 as the primary resistance mechanism for third-generation irreversible inhibitors, no potent drug targeting the EGFRC797S tertiary mutation has been approved. Consequently, the development of fourth-generation EGFR inhibitors is of paramount importance. In this article, we provide a comprehensive overview of the process of acquired EGFR mutations and recent advancements in medicinal chemistry related to acquired-resistant fourth-generation EGFR small-molecule inhibitors, with a particular focus on allosteric and reversible inhibitors designed to counteract the EGFRC797S mutation. We aim for these insights to inspire readers with innovative approaches in developing novel fourth-generation EGFR small-molecule inhibitors that effectively combat the EGFRC797S mutation.
| [1] | Herbst, R.S., Morgensztern, D. and Boshoff, C. (2018) The Biology and Management of Non-Small Cell Lung Cancer. Nature, 553, 446-454. https://doi.org/10.1038/nature25183 |
| [2] | Thai, A.A., Solomon, B.J., Sequist, L.V., Gainor, J.F. and Heist, R.S. (2021) Lung Cancer. The Lancet, 398, 535-554. https://doi.org/10.1016/S0140-6736(21)00312-3 |
| [3] | Nagano, T., Tachihara, M. and Nishimura, Y. (2018) Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy. Cells, 7, Article 212. https://doi.org/10.3390/cells7110212 |
| [4] | Shah, R. and Lester, J.F. (2020) Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer: A Clash of the Generations. Clinical Lung Cancer, 21, E216-E228. https://doi.org/10.1016/j.cllc.2019.12.003 |
| [5] | Bhatia, P., Sharma, V., Alam, O., Manaithiya, A., et al. (2020) Novel Quinazoline-Based EGFR Kinase Inhibitors: A Review Focusing on SAR and Molecular Docking Studies (2015-2019). European Journal of Medicinal Chemistry, 204, Article 112640. https://doi.org/10.1016/j.ejmech.2020.112640 |
| [6] | Li, D., Shimamura, T., et al. (2007) Bronchial and Peripheral Murine Lung Carcinomas Induced by T790M-L858R Mutant EGFR Respond to HKI-272 and Rapamycin Combination Therapy. Cancer Cell, 12, 81-93. https://doi.org/10.1016/j.ccr.2007.06.005 |
| [7] | Lu, X., Yu, L., Zhang, Z., et al. (2018) Targeting EGFRL858R/T790M and EGFRL858R/T790M/C797S Resistance Mutations in NSCLC: Current Developments in Medicinal Chemistry. Medicinal Research Reviews, 38, 1550-1581. https://doi.org/10.1002/med.21488 |
| [8] | Jackman, D.M., Yeap, B.Y., et al. (2006) Exon 19 Deletion Mutations of Epidermal Growth Factor Receptor Are Associated with Prolonged Survival in Non-Small-Cell Lung Cancer Patients Treated with Gefitinib or Erlotinib. Clinical Cancer Research, 12, 3908-3914. https://doi.org/10.1158/1078-0432.CCR-06-0462 |
| [9] | Yasuda, H., Kobayashi, S. and Costa, D.B. (2012) EGFR Exon 20 Insertion Mutations in Non-Small-Cell Lung Cancer: Preclinical Data and Clinical Implications. The Lancet Oncology, 13, E23-E31. https://doi.org/10.1016/S1470-2045(11)70129-2 |
| [10] | Ou, S.-H.I., Hong, J.-L., Christopoulos, P., Lin, H.M., Vincent, S., et al. (2023) Distribution and Detectability of EGFR Exon 20 Insertion Variants in NSCLC. Journal of Thoracic Oncology, 18, 744-754. https://doi.org/10.1016/j.jtho.2023.01.086 |
| [11] | Shaikh, M., Shinde, Y., Pawara, R., Noolvi, M., Surana, S., Ahmad, I. and Patel, H. (2021) Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer. Journal of Medicinal Chemistry, 65, 1008-1046. https://doi.org/10.1021/acs.jmedchem.1c00876 |
| [12] | Yu, H.A. and Pao, W. (2013) Afatinib—New Therapy Option for EGFR-Mutant Lung Cancer. Nature Reviews Clinical Oncology, 10, 551-552. https://doi.org/10.1038/nrclinonc.2013.154 |
| [13] | Zhou, W., Ercan, D., Chen, L., et al. (2009) Novel Mutant-Selective EGFR Kinase Inhibitors against EGFR T790M. Nature, 462, 1070-1074. https://doi.org/10.1038/nature08622 |
| [14] | Thress, K.S., Paweletz, C.P., Felip, E., et al. (2015) Acquired EGFR C797S Mutation Mediates Resistance to AZD9291 in Non-Small-Cell Lung Cancer Harboring EGFR T790M. Nature Medicine, 21, 560-562. https://doi.org/10.1038/nm.3854 |
| [15] | Chia, P.L., Do, H., Morey, A., Mitchell, P., Dobrovic, A. and John, T. (2016) Temporal Changes of EGFR Mutations and T790M Levels in Tumour and Plasma DNA Following AZD9291 Treatment. Lung Cancer, 98, 29-32. https://doi.org/10.1016/j.lungcan.2016.05.003 |
| [16] | Chen, L., Fu, W., Zheng, L., Liu, Z. and Liang, G. (2017) Recent Progress of Small-Molecule Epidermal Growth Factor Receptor (EGFR) Inhibitors Against C797S Resistance in Non-Small-Cell Lung Cancer. Journal of Medicinal Chemistry, 61, 4290-4300. https://doi.org/10.1021/acs.jmedchem.7b01310 |
| [17] | Xu, L., Xu, B., Wang, J., Gao, Y., He, X., Xie, T. and Ye, X.-Y. (2023) Recent Advances of Novel Fourth Generation EGFR Inhibitors in Overcoming C797S Mutation of Lung Cancer Therapy. European Journal of Medicinal Chemistry, 245, Article 114900. https://doi.org/10.1016/j.ejmech.2022.114900 |
| [18] | Hidaka, N., Iwama, E., Kubo, N., et al. (2017) Most T790M Mutations Are Present on the Same EGFR Allele as Activating Mutations in Patients with Non-Small-Cell Lung Cancer. Lung Cancer, 108, 75-82. https://doi.org/10.1016/j.lungcan.2017.02.019 |
| [19] | Kim, E.S. (2016) Olmutinib: First Global Approval. Drugs, 76, 1153-1157. https://doi.org/10.1007/s40265-016-0606-z |
| [20] | Popat, S. (2018) Osimertinib as First-Line Treatment in EGFR-Mutated Non-Small-Cell Lung Cancer. New England Journal of Medicine, 378, 192-193. https://doi.org/10.1056/NEJMe1714580 |
| [21] | Soria, J.-C., Ohe, Y., et al. (2018) Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. New England Journal of Medicine, 378, 113-125. https://doi.org/10.1056/NEJMoa1713137 |
| [22] | Hoffknecht, P., Tufman, A., Wehler, T., et al. (2015) Efficacy of the Irreversible ErbB Family Blocker Afatinib in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI)-Pretreated Non-Small-Cell Lung Cancer Patients with Brain Metastases or Leptomeningeal Disease. Journal of Thoracic Oncology, 10, 156-163. https://doi.org/10.1097/JTO.0000000000000380 |
| [23] | Patel, H., Pawara, R., Ansari, A. and Surana, S. (2017) Recent Updates on Third Generation EGFR Inhibitors and Emergence of Fourth Generation EGFR Inhibitors to Combat C797S Resistance. European Journal of Medicinal Chemistry, 142, 32-47. https://doi.org/10.1016/j.ejmech.2017.05.027 |
| [24] | Ward, R.A., Anderton, M.J., et al. (2013) Structure and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR). Journal of Medicinal Chemistry, 56, 7025-7048. https://doi.org/10.1021/jm400822z |
| [25] | Finlay, M.R.V., Anderton, M., Ashton, S., et al. (2014) Discovery of a Potent and Selective EGFR Inhibitor (AZD9291) of Both Sensitizing and T790M Resistance Mutations That Spares the Wild Type Form of the Receptor. Journal of Medicinal Chemistry, 57, 8249-8267. https://doi.org/10.1021/jm500973a |
| [26] | Zhao, H.-Y., Xi, X.-X., Xin, M. and Zhang, S.-Q. (2022) Overcoming C797S Mutation: The Challenges and Prospects of the Fourth-Generation EGFR-TKIs. Bioorganic Chemistry, 128, Article 106057. https://doi.org/10.1016/j.bioorg.2022.106057 |
| [27] | Yang, Z., Yang, N., Ou, Q., Xiang, Y., et al. (2018) Investigating Novel Resistance Mechanisms to Third-Generation EGFR Tyrosine Kinase Inhibitor Osimertinib in Non-Small-Cell Lung Cancer Patients. Clinical Cancer Research, 24, 3097-3107. https://doi.org/10.1158/1078-0432.CCR-17-2310 |
| [28] | Lu, C., Wei, X.-W., Wang, Z., et al. (2023) Allelic Context of EGFR C797X-Mutant Lung Cancer Defines Four Subtypes with Heterogeneous Genomic Landscape and Distinct Clinical Outcomes. Journal of Thoracic Oncology, 19, 601-612. https://doi.org/10.1016/j.jtho.2023.11.016 |
| [29] | 曹雨婷, 郭中原, 刘晓谦, 杨红, 高慧敏, 王智民. 表皮生长因子受体酪氨酸激酶抑制剂研究进展[J]. 中国药学杂志, 2023, 58(22): 2016-2027. |
| [30] | Niederst, M.J., Hu, H., Mulvey, H.E., Lockerman, E.L., Garcia, A.R., Piotrowska, Z., Sequist, L.V. and Engelman, J.A. (2015) The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies. Clinical Cancer Research, 21, 3924-3933. https://doi.org/10.1158/1078-0432.CCR-15-0560 |
| [31] | Blaquier, J.B., Ortiz-Cuaran, S., Ricciuti, B., Mezquita, L., Cardona, A.F. and Recondo, G. (2023) Tackling Osimertinib Resistance in EGFR-Mutant Non-Small-Cell Lung Cancer. Clinical Cancer Research, 29, 3579-3591. https://doi.org/10.1158/1078-0432.CCR-22-1912 |
| [32] | Guan, M., Xu, J. and Shi, Q. (2023) Molecular Determinants of Clinical Outcomes for Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer in Chinese Patients: A Retrospective Study. Cancer Genetics, 270-271, 32-38. https://doi.org/10.1016/j.cancergen.2022.11.005 |
| [33] | Wang, S., Song, Y. and Liu, D. (2017) EAI045: The Fourth-Generation EGFR Inhibitor Overcoming T790M and C797S Resistance. Cancer Letters, 385, 51-54. https://doi.org/10.1016/j.canlet.2016.11.008 |
| [34] | Karnik, K.S., Sarkate, A.P., Tiwari, S.V., Azad, R. and Wakte, P.S. (2021) Free Energy Perturbation Guided Synthesis with Biological Evaluation of Substituted Quinoline Derivatives as Small Molecule L858R/T790M/C797S Mutant EGFR Inhibitors Targeting Resistance in Non-Small-Cell Lung Cancer (NSCLC). Bioorganic Chemistry, 115, Article 105226. https://doi.org/10.1016/j.bioorg.2021.105226 |
| [35] | 邓燕莉, 王婕, 魏上斐, 翟鑫. 靶向变构位点的变构激酶抑制剂的研究进展[J]. 沈阳药科大学学报, 2023, 40(2): 248-257. |
| [36] | Wu, X.Y., Guo, Q., Li, Q.L., Wan, S.H., et al. (2021) Molecular Mechanism Study of EGFR Allosteric Inhibitors Using Molecular Dynamics Simulations and Free Energy Calculations. Journal of Biomolecular Structure & Dynamics, 40, 5848-5857. https://doi.org/10.1080/07391102.2021.1874530 |
| [37] | Jia, Y., Yun, C.-H., et al. (2016) Overcoming EGFR(T790M) and EGFR(C797S) Resistance with Mutant-Selective Allosteric Inhibitors. Nature, 534, 129-132. https://doi.org/10.1038/nature17960 |
| [38] | Lee, S., Kim, J., Duggirala, K.B., Go, A., Shin, I., Cho, B.C., Choi, G., Chae, C.H. and Lee, K. (2018) Allosteric Inhibitor TREA‐0236 Containing Non‐Hydrolysable Quinazoline‐4‐One for EGFR T790M/C797S Mutants Inhibition. Bulletin of the Korean Chemical Society, 39, 895-898. https://doi.org/10.1002/bkcs.11491 |
| [39] | To, C., Jang, J., Chen, T., Park, E., Mushajiang, M., de Clercq, D.J.H., Xu, M., Wang, S., et al. (2019) Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor. Cancer Discovery, 9, 926-943. https://doi.org/10.1158/2159-8290.CD-18-0903 |
| [40] | de Clercq, D.J.H., Heppner, D.E., To, C., et al. (2019) Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors. ACS Medicinal Chemistry Letters, 10, 1549-1553. https://doi.org/10.1021/acsmedchemlett.9b00381 |
| [41] | Li, Q., Zhang, T., Li, S., et al. (2019) Discovery of Potent and Noncovalent Reversible EGFR Kinase Inhibitors of EGFRL858R/T790M/C797S. ACS Medicinal Chemistry Letters, 10, 869-873. https://doi.org/10.1021/acsmedchemlett.8b00564 |
| [42] | Wittlinger, F., Heppner, D.E., To, C., et al. (2021) Design of a “Two-In-One” Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites. Journal of Medicinal Chemistry, 65, 1370-1383. https://doi.org/10.1021/acs.jmedchem.1c00848 |
| [43] | Dou, D., Wang, J., Qiao, Y., et al. (2022) Discovery and Optimization of 4-Anilinoquinazoline Derivatives Spanning ATP Binding Site and Allosteric Site as Effective EGFR-C797S Inhibitors. European Journal of Medicinal Chemistry, 244, Article 114856. https://doi.org/10.1016/j.ejmech.2022.114856 |
| [44] | Hu, L., Shi, S., Song, X., et al. (2024) Identification of Novel Aminopyrimidine Derivatives for the Treatment of Mutant NSCLC. European Journal of Medicinal Chemistry, 265, Article 116074. https://doi.org/10.1016/j.ejmech.2023.116074 |
