|
|
靶向激酶的PROTAC研究进展
|
Abstract:
蛋白激酶(PK)失调与多种疾病过程相关，多种蛋白激酶抑制剂得被开发用以治疗疾病。蛋白激酶抑制剂虽然得到了很好的研究，但仍然面临耐药性及选择性不高等挑战。蛋白水解靶向嵌合体(PROTAC)这一技术的开发，有效地解决了蛋白激酶抑制剂耐药以及低选择性等问题，从而得到了广泛的关注。目前，已经有多种激酶PROTAC项目进入临床前和临床研究。本文综述了专利及文献报道的靶向蛋白激酶的PROTAC研究进展。总结并展望靶向蛋白质降解技术的发展前景，及面临的机遇与挑战。
Protein kinase (PK) disorders are associated with a variety of disease processes, and multiple pro-tein kinase inhibitors have been developed to treat disease. Although protein kinase inhibitors are well developed, there still are challenges of drug resistance and low selectivity. The development of proteolytic targeted chimera (PROTAC) technology has effectively solved the drug resistance of the protein kinase inhibitor and side effects caused by low selectivity, which has received widespread attention. Currently, a variety of kinase PROTAC projects have entered preclinical and clinical stud-ies. This article reviews the research progress of patented and literature-reported PROTAC target-ing protein kinases. Summarize and look forward to the development prospects of targeted protein degradation technology, as well as the opportunities and challenges.
| [1] | Kroemer, G., Marino, G. and Levine, B. (2010) Autophagy and the Integrated Stress Response. Molecular Cell, 40, 280-293. https://doi.org/10.1016/j.molcel.2010.09.023 |
| [2] | Pickart, C.M. (2000) Ubiquitin in Chains. Trends in Biochemical Sciences, 25, 544-548.
https://doi.org/10.1016/S0968-0004(00)01681-9 |
| [3] | Coleman, K.G. and Crews, C.M. (2018) Proteoly-sis-Targeting Chimeras: Harnessing the Ubiquitin-Proteasome System to Induce Degradation of Specific Target Proteins. Annual Review of Cancer Biology, 2, 41-58.
https://doi.org/10.1146/annurev-cancerbio-030617-050430 |
| [4] | Martin-Acosta, P. and Xiao, X. (2021) PROTACs to Address the Challenges Facing Small Molecule Inhibitors. European Journal of Medicinal Chemistry, 210, Article ID: 112993. https://doi.org/10.1016/j.ejmech.2020.112993 |
| [5] | Soltan, O.M., Shoman, M.E., Abdel-Aziz, S.A., et al. (2021) Molecular Hybrids: A Five-Year Survey on Structures of Multiple Targeted Hybrids of Protein Kinase Inhibitors for Cancer Therapy. European Journal of Medicinal Chemistry, 225, Article ID: 113768. https://doi.org/10.1016/j.ejmech.2021.113768 |
| [6] | Yang, Y.Q., Gao, H.Y., Sun, X.Y., et al. (2020) Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects. Journal of Me-dicinal Chemistry, 63, 8567-8583.
https://doi.org/10.1021/acs.jmedchem.0c00967 |
| [7] | Jiang, L., Wang, Y.T., Li, Q., et al. (2021) Design, Synthesis, and Biological Evaluation of Bcr-Abl PROTACs to Overcome T315I Mutation. Acta Pharmaceutica Sinica B, 11, 1315-1328. https://doi.org/10.1016/j.apsb.2020.11.009 |
| [8] | Liu, H.X., Ding, X.Y., Liu, L.Y., et al. (2021) Dis-covery of Novel BCR-ABL PROTACs Based on the Cereblon E3 Ligase Design, Synthesis, and Biological Evaluation. European Journal of Medicinal Chemistry, 223, Article ID: 113645. https://doi.org/10.1016/j.ejmech.2021.113645 |
| [9] | Crews, C., Toure, M., Ko, E., et al. (2017) Proteolysis Target-ing Chimera Compounds and Methods of Preparing and Using Same. Patent WO2017079267A1. |
| [10] | Lai, A.C., Toure, M., Hellerschmied, D., Salami, J., Jaime-Figueroa, S., Ko, E., Hines, J. and Crews, C.M. (2016) Modular PROTAC De-sign for the Degradation of Oncogenic BCR-ABL. Angewandte Chemie International Edition in English, 55, 807-810. https://doi.org/10.1002/anie.201507634 |
| [11] | Gabizon, R. and London, N. (2020) A Fast and Clean BTK Inhibitor. Journal of Medicinal Chemistry, 63, 5100-5101.
https://doi.org/10.1021/acs.jmedchem.0c00597 |
| [12] | Tasso, B., Spallarossa, A., Russo, E. and Brullo, C. (2021) The Development of BTK Inhibitors: A Five-Year Update. Molecules, 26, 7411. https://doi.org/10.3390/molecules26237411 |
| [13] | ShorerArbel, Y., Katz, B.-Z., Gabizon, R., Shraga, A., Bronstein, Y., Kamdjou, T., Globerson Levin, A., Perry, C., Avivi, I., London, N. and Herishanu, Y. (2021) Proteolysis Targeting Chimeras for BTK Efficiently Inhibit B-Cell Receptor Signaling and Can Overcome Ibrutinib Resistance in CLL Cells. Frontiers in Oncology, 11, Article ID: 646971.
https://doi.org/10.3389/fonc.2021.646971 |
| [14] | Sun, Y., Zhao, X., Ding, N., et al. (2018) PROTAC-Induced BTK Degradation as a Novel Therapy for Mutated BTK C481S Induced Ibrutinib-Resistant B-Cell Malignancies. Cell Re-search, 28, 779-781.
https://doi.org/10.1038/s41422-018-0055-1 |
| [15] | Sun, Y., Ding, N., Song, Y., et al. (2019) Degradation of Bru-ton’s Tyrosine Kinase Mutants by PROTACs for Potential Treatment of Ibrutinib-Resistant Non-Hodgkin Lymphomas. Leukemia, 33, 2105-2110.
https://doi.org/10.1038/s41375-019-0440-x |
| [16] | Dobrovolsky, D., Wang, E.S., Morrow, S., Leahy, C., Faust, T., Nowak, R.P., Donovan, K.A., Yang, G., Li, Z.N., Fischer, E.S., Treon, S.P., Weinstock, D.M. and Gray, N.S. (2019) Bruton Tyrosine Kinase Degradation as a Therapeutic Strategy for Cancer. Blood, 133, 952-961. https://doi.org/10.1182/blood-2018-07-862953 |
| [17] | Lu, Y. and Sun, H.Y. (2020) Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK). Journal of Medicinal Chemistry, 63, 14382-14403. https://doi.org/10.1021/acs.jmedchem.0c01248 |
| [18] | Crews, C.M., Cromm, P.M. and Crew, A.P. (2020) Prepara-tion of Bifunctional Substituted Pyrimidines as Modulators of FAK Proteolyse. Patent WO2020023851A1. |
| [19] | Gray, N.S., Jiang, B., Nabet, B., et al. (2020) Degradation of FAK or FAC and ALK by Conjugation of FAC and ALK Inhibi-tors with E3 Ligase Ligands and Methods of Use. Patent WO2020069117A1. |
| [20] | Ito, K., Park, S.H., Katsyv, I., et al. (2017) PTK6 Regulates Growth and Survival of Endocrine Therapy-Resistant ER+ Breast Cancer Cells. NPJ Breast Cancer, 3, 45. https://doi.org/10.1038/s41523-017-0047-1 |
| [21] | Gilic, M.B. and Tyner, A.L. (2020) Targeting Pro-tein Tyrosine Kinase 6 in Cancer. Biochimica et Biophysica Acta (BBA)—Reviews on Cancer, 1874, Article ID: 188432. https://doi.org/10.1016/j.bbcan.2020.188432 |
| [22] | Jin, J., Irie, H., Liu, J., et al. (2020) Preparation as Heterocyclic Compounds as Protein Tyrosine Kinase 6 (PTK6) Degradation/Disruption Compounds and Methods of Use. Patent WO2020010204A1. |
| [23] | Matheson, C.J., Backos, D.S. and Reigan, P. (2016) Targeting WEE1 Kinase in Cancer. Trends in Pharmacological Sciences, 37, 872-881. https://doi.org/10.1016/j.tips.2016.06.006 |
| [24] | Li, Z.N., Li, Z., Pinch, B.J., Olson, C.M., et al. (2020) Development and Characterization of a Wee1 Kinase Degrader. Cell Chemical Bi-ology, 27, 57-65.e9. https://doi.org/10.1016/j.chembiol.2019.10.013 |
| [25] | Bennett, J. and Starczynowski, D.T. (2022) IRAK1 and IRAK4 as Emerging Therapeutic Targets in Hematologic Malignancies. Current Opinion in Hema-tology, 29, 8-19. https://doi.org/10.1097/MOH.0000000000000693 |
| [26] | Mainolfi, N., Ji, N., Kluge, A.F., et al. (2020) Preparation of Bifunctional Compounds as IRAK Degraders and Uses Thereof. Patent WO2020113233A1. |
| [27] | Aoki, Y. and Matsubara, Y. (2013) Ras/MAPK Syndromes and Childhood Hemato-Oncological Diseases. International Journal of Hematologym, 97, 30-36. https://doi.org/10.1007/s12185-012-1239-y |
| [28] | Dietrich, J., Gokhale, V., Wang, X.D., et al. (2010) Application of a Novel [3+2] Cycloaddition Reaction to Prepare Substituted Imidazoles and Their Use in the Design of Potent DFG-Outallosteric B-Rafinhibitors. Bioorganic& Medicinal Chemistry, 18, 292-304. https://doi.org/10.1016/j.bmc.2009.10.055 |
| [29] | Thabit, M.G., Mostafa, A.S., Selim, K.B., et al. (2020) Design, Synthesis and Molecular Modeling of Phenyl Dihydropyridazinone Derivatives as B-Raf Inhibitors with Anticancer Ac-tivity. Bioorganic Chemistry, 103, Article ID: 104148. https://doi.org/10.1016/j.bioorg.2020.104148 |
| [30] | Crew, A.P., Hornberger, K.R., Wang, J., et al. (2020) Polycyclic Compounds and Methods for the Targeted Degradation of Rapidly Accelerated Fibrosarcoma Polypeptides. Patent WO2020051564A1. |
| [31] | Huang, J.H., Wang, X.R, Dong, R.N., et al. (2021) Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin- 2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies. Journal of Medicinal Chemistry, 64, 12548-12571.
https://doi.org/10.1021/acs.jmedchem.1c00271 |
| [32] | Freeman-Cook, K.D., Hoffman, R.L., Behenna, D.C., et al. (2021) Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer. Journal of Medicinal Chemistry, 64, 9056-9077. |
| [33] | Gray, N., Zhang, T., Olson, C.M., et al. (2017) Degradation of Cyclin-Dependent Kinase 9 (cdk9) by Conjugation of cdk9 Inhibitors with e3 Ligase Ligand and Methods of Use. Patent WO2017185031A1. |
| [34] | Gray, N.S., Jiang, B., Zhang, T., et al. (2020) Degradation of Cyclin-Dependent Kinase 4/6 (cdk4/6) by Conjugation of cdk4/6 Inhibitors with E3 Ligase Ligand and Methods of Use. Patent WO2020023480A1. |
| [35] | Salvino, J., Calabretta, B., De Dominici, M., et al. (2020) Preparation of Pyrimidine Derivatives as Proteolysis-Targeting Chimeras (PROTACs). Patent WO2020092662A1. |
| [36] | Gray, N., Zhang, T., Olson, C.M., et al. (2017) Degradation of Cyclin-Dependent Kinase 9 (cdk9) by Conjugation of cdk9 Inhibitors with E3 Ligase Ligand and Methods of Use. Patent WO2017185023A1. |
| [37] | Taft, J., Markson, M., Legarda, D., et al. (2021) Human TBK1 Deficiency Leads to Autoin-flammation Driven by TNF-Induced Cell Death. Cell, 184, 4447-4463.e20. https://doi.org/10.1016/j.cell.2021.07.026 |
| [38] | Crew, A.P., Wang, J., Dong, H., et al. (2016) Preparation of PROTAC Compounds as TANK-Binding Kinase 1 Inhibitors for Modulation of Proteolysis and Associated Methods of Use. Patent WO2016197114A1. |
| [39] | Zheng, M.Z., Huo, J.F., Gu, X.X., et al. (2021) Rational Design and Synthesis of Novel Dual PROTACs for Simultaneous Degradation of EGFR and PARP. Journal of Medicinal Chemistry, 64, 7839-7852.
https://doi.org/10.1021/acs.jmedchem.1c00649 |
