|
|
Pharmacy Information 2023
ATR小分子抑制剂的研究进展
|
Abstract:
共济失调毛细血管扩张和Rad3相关激酶(ATR)是DNA损伤反应(DDR)的重要调节因子，尤其是对复制压力(RS)的反应。由于DNA损伤和RS是基因组不稳定性的主要来源，选择性抑制ATR是癌症治疗的一种有前途的新方法。本文综述了ATR的结构功能以及ATR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。
Ataxia-telangiectasia and Rad3-related kinase (ATR) are important regulators of the DNA damage response (DDR), particularly in response to replication stress (RS). As DDR and RS are major sources of genomic instability, selective inhibition of ATR is a promising new approach for cancer therapy. This article reviews the structural function of ATR and the progress of research on small molecule inhibitors of ATR in order to provide theoretical assistance and guidance for further research in this field.
| [1] | Choi, W.Y. and Lee, E.S. (2022) Therapeutic Targeting of DNA Damage Response in Cancer. International Journal of Molecular Sciences, 23, 1701. https://doi.org/10.3390/ijms23031701 |
| [2] | Desai, A., Yan, Y. and Gerson, S.L. (2018) Advances in Therapeutic Targeting of the DNA Damage Response in Cancer. DNA Repair, 66-67, 24-29. https://doi.org/10.1016/j.dnarep.2018.04.004 |
| [3] | Jackson, S.P. and Helleday, T. (2016) Drugging DNA Repair. Science, 352, 1178-1179.
https://doi.org/10.1126/science.aab0958 |
| [4] | Roos, W.P., Thomas, A.D. and Kaina, B. (2016) DNA Damage and the Balance between Survival and Death in Cancer Biology. Nature Reviews Cancer, 16, 20-33. https://doi.org/10.1038/nrc.2015.2 |
| [5] | Poehlmann, A. and Roessner, A. (2010) Importance of DNA Damage Checkpoints in the Pathogenesis of Human Cancers. Pathology Research and Practice, 206, 591-601. https://doi.org/10.1016/j.prp.2010.06.006 |
| [6] | Yazinski, S.A. and Zou, L. (2016) Functions, Regulation, and Therapeutic Implications of the ATR Checkpoint Pathway. Annual Review of Genetics, 50, 155-173. https://doi.org/10.1146/annurev-genet-121415-121658 |
| [7] | Cimprich, K.A. and Cortez, D. (2008) ATR: An Es-sential Regulator of Genome Integrity. Nature Reviews Molecular Cell Biology, 9, 616-627. https://doi.org/10.1038/nrm2450 |
| [8] | Foote, K.M., Lau, A. and Nissink, J.W.M. (2015) Drugging ATR: Progress in the Development of Specific Inhibitors for the Treatment of Cancer. Future Medicinal Chemistry, 7, 873-891. https://doi.org/10.4155/fmc.15.33 |
| [9] | Taylor, E.M. and Lindsay, H.D. (2016) DNA Replication Stress and Cancer: Cause or Cure? Future Oncology, 12, 221-237. https://doi.org/10.2217/fon.15.292 |
| [10] | Lecona, E. and Fernan-dez-Capetillo, O. (2018) Targeting ATR in Cancer. Nature Reviews Cancer, 18, 586-595.
https://doi.org/10.1038/s41568-018-0034-3 |
| [11] | Cimprich, K.A., Shin, T.B., Keith, C.T., et al. (1996) cDNA Cloning and Gene Mapping of a Candidate Human Cell Cycle Checkpoint Protein. Proceedings of the National Academy of Sciences of the United States of America, 93, 2850-2855. https://doi.org/10.1073/pnas.93.7.2850 |
| [12] | Dumaz, N. and Meek, D.W. (1999) Serine15 Phosphorylation Stimulates p53 Transactivation but Does Not Directly Influence In-teraction with HDM2. EMBO, 18, 7002-7010. https://doi.org/10.1093/emboj/18.24.7002 |
| [13] | Halazonetis, T.D., Gorgoulis, V.G. and Bartek, J. (2008) An Oncogene-Induced DNA Damage Model for Cancer Development. Science, 319, 1352-1355. https://doi.org/10.1126/science.1140735 |
| [14] | Hu, S., Hui, Z., Duan, J., Garrido, C., Xie, T. and Ye, X.Y. (2022) Discovery of Small-Molecule ATR Inhibitors for Potential Cancer Treatment: A Patent Review from 2014 to Present. Expert Opinion on Therapeutic Patents, 32, 401-421. https://doi.org/10.1080/13543776.2022.2027911 |
| [15] | Ronald, K., Jean-Damien, C., Steven, D., Davis, C., O’Donnell, M., Storck, P., et al. (2019) Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine(VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor. Journal of Medicinal Chemistry, 62, 5547-5561.
https://doi.org/10.1021/acs.jmedchem.9b00426 |
| [16] | Kevin, F., Willem, N., Thomas, M., et al. (2018) Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent. Journal of Medicinal Chemistry, 61, 9889-9907. https://doi.org/10.1021/acs.jmedchem.8b01187 |
| [17] | Francesco, D., et al. (2019) Heterocyclic Inhibitors of ATR Kinase: WO2019014618. |
| [18] | Zhao, Y.P., Liu, B., Jiang, Y.Y., et al. (2021) 2,4,6-Tri-substituted Pyrimidine Com-pounds as ATR Kinase Inhibitors: WO2021233376. 2021-11-25. |
| [19] | Qian, W.Y., Wang, J., Li, J., Li, J., et al. (2019) ATR Inhibitor and Application Thereof: WO2019154365. 2019-08-15. |
| [20] | Francesco, D., et al. (2019) Heterocyclic Inhibitors of ATR Kinase: WO2019178590. 2019-09-19. |
| [21] | Shan, B., Hou, B., Yu, W.H., et al. (2022) ATR Inhibi-tors and Uses Thereof: WO2022002245. 2022-01-06. |
| [22] | Fang, K. and Chen, S.H. (2021) Fluoropyrrolopyridine Compound and Application Thereof: WO2021238999. 2021-12-02. |
| [23] | Bin, H.C., Chen, P., Wu, M., et al. (2022) Discovery of a Potent and Highly Selective Inhibitor of Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase: Structural Activity Relationship and Antitumor Activity both in Vitro and in Vivo. European Journal of Medicinal Chem-istry, 232, Article ID: 114187.
https://doi.org/10.1016/j.ejmech.2022.114187 |
| [24] | Chen, P., Bin, H.C., Jiao, Y., et al. (2022) Discovery of 6,7-Dihydro-5H-pyrrolo[3,4-d] Pyrimidine Derivatives as a New Class of ATR Inhibitors. Bioorganic & Medicinal Chemistry Letters, 63, Article ID: 128651.
https://doi.org/10.1016/j.bmcl.2022.128651 |
| [25] | Li, X., Chen, Y., Cai, G.D., et al. (2022) Imidazopyrimidine De-rivative, Preparation Method Therefor and Medical Use Thereof: WO2022002243. 2022-01-06. |
| [26] | 李心, 杨芳, 冯斌强, 等. 稠合嘧啶类衍生物、其制备方法及其在医药上的应用[P]. 中国, CN113135942. 2021-07-20. |
| [27] | Li, X. Zeng, C.G., He, F., et al. (2021) Fused Heteroaryl Derivative, Preparation Method Therefor, and Application Thereof in Medicine: WO2021143821. 2021-07-22. |
| [28] | Zhao, Z.M., Yang, W., Wu, Z.H., et al. (2020) Heterocyclic Fused Py-rimidine Derivative, Pharmaceutical Composition Thereof, and Application Thereof: WO2020103897. 2020-05-28. |
| [29] | Lücking, U., Wortmann, L., Wengner, A.M., et al. (2020) Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models. Journal of Medicinal Chemistry, 63, 7293-7325. https://doi.org/10.1016/j.bmcl.2022.128651 |
| [30] | Wengner, A.M., Siemeister, G., Lücking, U., et al. (2020) The Novel ATR Inhibitor BAY 1895344 Is Efficacious as Monotherapy and Combined with DNA Damage-Inducing or Repair-Compromising Therapies in Preclinical Cancer Models. Molecular Cancer Therapeu-tics, 19, 26-38. https://doi.org/10.1158/1535-7163.MCT-19-0019 |
| [31] | Yap, T.A., Tan, D.S.P., Terbuch, A., et al. (2021) First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Pa-tients with Advanced Solid Tumors. Cancer Discovery, 11, 80-91.
https://doi.org/10.1158/2159-8290.CD-20-0868 |
| [32] | 刘金明, 张浩亮, 何婷, 等. 一种取代吡啶并并[3,4-b]吡嗪-2(1H)-酮化合物、其制备方法和用途[P]. 中国, CN111848605. 2020-10-30. |
| [33] | Burgdorf, L. and Tsaklakidis, C. (2020) 5-Morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives: WO2020049017. 2020-03-12. |
| [34] | 吴颢, 沈益飞, 姚智理, 等. ATR抑制剂及其在医药上的应用[P]. 中国, CN112851668. 2021-05-28. |
| [35] | Li, X., Dong, H.D., Bai, D.D., et al. (2021) Pyrazolo-Heteroaryl Derivative, Preparation Method Therefor, and Medical Use Thereof: WO2021098811. 2021-05-27. |
| [36] | Shan, B., Hou, B., Yu, W.H., et al. (2022) Atr Inhibitors and Uses Thereof: WO2022028598. 2022-02-10. |
| [37] | Cai, S.X., Tian, Y. and Wang, X.Z. (2020) Substituted Fused Heteroaromatic Bicyclic Compounds as Kinase Inhibitors and the Use Thereof: WO2020259601. 2020-12-30. |
| [38] | Cheng, C., Zhao, Y.P., Wang, H.J., et al. (2022) Pyrazolopyrimidine Compound Used as Atr Kinase Inhibitor: WO2022012484. 2022-01-20. |
| [39] | Roulston, A., Zimmermann, M., Papp, R., et al. (2022) RP-3500: A Novel, Potent, and Selective ATR Inhibitor That Is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors. Molecular Cancer Therapeutics, 21, 245-256. https://doi.org/10.1158/1535-7163.MCT-21-0615 |
| [40] | 刘晓辉, 刘凤涛, 高大新. 三杂环衍生物、其药物组合物及应用[P]. 中国, CN114369096. 2022-04-19. |
| [41] | Wang, S.H., Yang, C.D. and Chen, S.H. (2022) Class of 1,7-Naphthyridine Compounds: WO2022063308. 2022-03-31. |
| [42] | Jo, U., Senatorov, I.S., Zimmermann, A., et al. (2021) Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells with Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents. Molecular Cancer Therapeutics, 20, 1431-1441. https://doi.org/10.1158/1535-7163.MCT-20-1026 |
| [43] | Yap, T.A., Tolcher, A.W., Plummer, E.R., et al. (2021) A First-in-Human Phase I Study of ATR Inhibitor M1774 in Patients with Solid Tumors. Journal of Clinical Oncology, 39, TPS3153.
https://doi.org/10.1200/JCO.2021.39.15_suppl.TPS3153 |
| [44] | Paul, B., Robert, A., Xianming J, et al. (2015) Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5-a]pyrazines as ATR Inhibitors. ACS Medicinal Chemistry Letters, 6, 37-41.
https://doi.org/10.1021/ml500353p |
| [45] | Paul B, Yue P, Yipin L, et al. (2015) Structure-Based Drug Design of Novel, Potent, and Selective Azabenzimidazoles (ABI) as ATR Inhibitors. ACS Medicinal Chemistry Letters, 6, 42-46. https://doi.org/10.1021/ml500352s |
| [46] | 王伟, 曾宏, 巩晓明, 等. 一类吡嗪酮衍生物、其制备及其应用[P]. 中国, CN114591324. 2022-06-07. |
