Proteolysis Targeted Chimera “PROTAC”

Abstract

As an emerging therapeutic strategy, Proteolysis Targeted Chimera (PROTAC) is a bifunctional molecule that leads to degradation rather than inhibition of the activity of a specific target protein. PROTAC molecules consist of three parts, a target protein ligand, E3 ligase, and a linker, and use the ubiquitin proteosome system in the cell to cleave different target proteins. PROTAC technology has advanced significantly in the last two decades and has become a breakthrough in cancer treatment by attracting attention today. While the PROTAC approach is also causing a devastating change in drug discovery studies, the many potential advantages and extraordinary challenges that lie ahead of this technology are discussed. In this review, information on the advantages and challenges of PROTAC that will contribute to cancer treatment and drug discovery studies is given by comparing it with traditional and modern treatment methods.

Keywords

• PROTAC
• UPS
• Drug discovery
• Cancer treatment

Kanser Tedavisinde Yeni Bir Yaklaşım “Proteoliz Hedefli Kimera”

Öz

Gelişmekte olan terapötik bir strateji olarak Proteoliz Hedefli Kimera (PROTAC), belirli bir hedef protein aktivitesinin inhibisyonundan ziyade, degredasyonuna yol açan iki işlevli bir moleküldür. PROTAC molekülleri, bir hedef protein ligandı, E3 ligaz ve bir bağlayıcı olmak üzere üç kısımdan oluşmakta ve farklı hedef proteinleri parçalamak için hücredeki ubikutin proteozom sistemini kullanmaktadır. PROTAC teknolojisi, son yirmi yılda önemli ölçüde ilerlemiş ve günümüzde de dikkatleri üzerinde toplayarak kanser tedavisinde çığır açabilecek bir dönüm noktası haline gelmiştir. PROTAC yaklaşımı aynı zamanda ilaç keşif çalışmalarında yıkıcı bir değişikliğe sebep olmakla birlikte bu teknolojinin önünde yatan birçok potansiyel avantaj ve olağanüstü zorluklar tartışılmaktadır. Bu derlemede, PROTAC’ın geleneksel ve modern tedavi yöntemleri ile karşılaştırılarak, kanser tedavisine ve ilaç keşif çalışmalarına katkı sağlayacak avantaj ve zorluklarına yönelik bilgilere yer verilmektedir.

Anahtar Kelimeler

• PROTAC
• UPS
• İlaç keşfi
• Kanser tedavisi

Kaynakça

1. Alabi, S., Jaime-Figueroa, S., Yao, Z., Gao, Y., Hines, J., Samarasinghe, K. T. G., Vogt, L., Rosen, N., & Crews, C. M. (2021). Mutant-selective degradation by BRAF-targeting PROTACs. Nature Communications, 12(1), 1–11. https://doi.org/10.1038/s41467-021-21159-7
2. Albitar, L., Carter, M. B., Davies, S., & Leslie, K. K. (2007). Consequences of the loss of p53, RB1, and PTEN: Relationship to gefitinib resistance in endometrial cancer. Gynecologic Oncology, 106(1), 94–104. ttps://doi.org/10.1016/j.ygyno.2007.03.006
3. Amiri-Kordestani, L., Basseville, A., Kurdziel, K., Fojo, A. T., & Bates, S. E. (2012). Targeting MDR in breast and lung cancer: Discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resistance Updates, 15(1–2), 50–61. https://doi.org/10.1016/j.drup.2012.02.002
4. Bakhache, W., Neyret, A., McKellar, J., Clop, C., Bernard, E., Weger-Lucarelli, J., & Briant, L. (2019). Fatty acid synthase and stearoyl-CoA desaturase-1 are conserved druggable cofactors of Old World Alphavirus genome replication. Antiviral Research, 172(July), 104642. https://doi.org/10.1016/j.antiviral.2019.104642
5. Barfeld, S. J., Urbanucci, A., Itkonen, H. M., Fazli, L., Hicks, J. L., Thiede, B., Rennie, P. S., Yegnasubramanian, S., DeMarzo, A. M., & Mills, I. G. (2017). c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks. EBioMedicine, 18, 83–93. https://doi.org/10.1016/j.ebiom.2017.04.006
6. Békés, M., Langley, D. R., & Crews, C. M. (2022). PROTAC targeted protein degraders: the past is prologue. Nature Reviews Drug Discovery, 21(3), 181–200. https://doi.org/10.1038/s41573-021-00371https://www.reactionbiology.com/services/target-specific-assays/targeted-protein-degradation (23.02.2022)
7. Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Jeffrey, L., Zinn, N., Grandi, P., Shimamura, S., Bergamini, G., Bantscheff, M., Cox, C., Gordon, D. A., Willard, R. R., Flanagan, J. J., … Craig, M. (2015). HHS Public Access. 11(8), 611–617. https://doi.org/10.1038/nchembio.1858.Catalytic
8. Buhimschi, A. D., Armstrong, H. A., Toure, M., Jaime-Figueroa, S., Chen, T. L., Lehman, A. M., Woyach, J. A., Johnson, A. J., Byrd, J. C., & Crews, C. M. (2018). Targeting the C481S Ibrutinib-Resistance Mutation in Bruton’s Tyrosine Kinase Using PROTAC-Mediated Degradation. Biochemistry, 57(26), 3564–3575. https://doi.org/10.1021/acs.biochem.8b00391

9. Burslem, G. M., Schultz, A. R., Bondeson, D. P., Eide, C. A., Stevens, S. L. S., Druker, B. J., & Crews, C. M. (2019). Targeting BCR-ABL1 in chronic myeloid leukemia by PROTAC-mediated targeted protein degradation. Cancer Research, 79(18), 4744–4753. https://doi.org/10.1158/0008-5472.CAN-19-1236
10. Burslem, G. M., Smith, B. E., Lai, A. C., Jaime-Figueroa, S., McQuaid, D. C., Bondeson, D. P., Toure, M., Dong, H., Qian, Y., Wang, J., Crew, A. P., Hines, J., & Crews, C. M. (2018). The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. Cell Chemical Biology, 25(1), 67-77.e3. https://doi.org/10.1016/j.chembiol.2017.09.009
11. Chen, Y., & Jin, J. (2020). The application of ubiquitin ligases in the PROTAC drug design. Acta Biochimica et Biophysica Sinica, 52(7), 776–790. https://doi.org/10.1093/ABBS/GMAA053
12. Churcher, I. (2018). Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? Journal of Medicinal Chemistry, 61(2), 444–452. https://doi.org/10.1021/acs.jmedchem.7b01272
13. Cimas, F. J., Niza, E., Juan, A., Noblejas-López, M. D. M., Bravo, I., Lara-Sanchez, A., Alonso-Moreno, C., & Ocaña, A. (2020). Controlled delivery of bet-protacs: In vitro evaluation of MZ1-loaded polymeric antibody conjugated nanoparticles in breast cancer. Pharmaceutics, 12(10), 1–11. https://doi.org/10.3390/pharmaceutics12100986
14. Collins, G. A., & Goldberg, A. L. (2017). The Logic of the 26S Proteasome. Cell, 169(5), 792–806. https://doi.org/10.1016/j.cell.2017.04.023
15. Dale, B., Cheng, M., Park, K. S., Kaniskan, H. Ü., Xiong, Y., & Jin, J. (2021). Advancing targeted protein degradation for cancer therapy. Nature Reviews Cancer, 21(10), 638–654. https://doi.org/10.1038/s41568-021-00365-x
16. DeGruttola, V., Dix, L., D’Aquila, R., Holder, D., Phillips, A., Ait-Khaled, M., Baxter, J., Clevenbergh, P., Hammer, S., Harrigan, R., Katzenstein, D., Lanier, R., Miller, M., Para, M., Yerly, S., Zolopa, A., Murray, J., Patick, A., Miller, V., … Mellors, J. (2000). The relation between baseline HIV drug resistance and response to antiretroviral therapy: Re-analysis of retrospective and prospective studies using a standardized data analysis plan. Antiviral Therapy, 5(1), 41–48.
17. Fang, Y., Liao, G., & Yu, B. (2020). Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy: advances and perspectives. Acta Pharmaceutica Sinica B, 10(7), 1253–1278. https://doi.org/10.1016/j.apsb.2020.01.003
18. Farnaby, W., Koegl, M., McConnell, D. B., & Ciulli, A. (2021). Transforming targeted cancer therapy with PROTACs: A forward-looking perspective. Current Opinion in Pharmacology, 57, 175–183. https://doi.org/10.1016/j.coph.2021.02.009
19. Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017). Structural basis of PROTAC cooperative recognition for selective protein degradation Accession codes Atomic coordinates and structure factors for hsBrd4 BD2-MZ1-hsVHL-hsEloC-hsEloB have been deposited in the Protein Data Bank (PDB) under accession number. Nat Chem Biol, 13(5), 514–521. https://doi.org/10.1038/nchembio.2329.
20. Gao, H., Sun, X., & Rao, Y. (2020). PROTAC Technology: Opportunities and Challenges [Article-commentary]. ACS Medicinal Chemistry Letters, 11(3), 237–240. https://doi.org/10.1021/acsmedchemlett.9b00597
21. Gao, H., Zheng, C., Du, J., Wu, Y., Sun, Y., Han, C., Kee, K., & Rao, Y. (2020). FAK-targeting PROTAC as a chemical tool for the investigation of non-enzymatic FAK function in mice. Protein and Cell, 11(7), 534–539. https://doi.org/10.1007/s13238-020-00732-8
22. Guang-Wei Zhang, Li Shen2,3, Wen Zhong2, Ying Xiong1,*, Li I. Zhang2,3,*, and Huizhong W. Tao2,3,*, & et al., C. (2016). HHS Public Access. Physiology & Behavior, 176(1), 139–148. https://doi.org/10.1021/acs.jmedchem.9b00846.Simple
23. Han, X., Zhao, L., Xiang, W., Qin, C., Miao, B., Xu, T., Wang, M., Yang, C. Y., Chinnaswamy, K., Stuckey, J., & Wang, S. (2019). Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands. Journal of Medicinal Chemistry, 62(24), 11218–11231. https://doi.org/10.1021/acs.jmedchem.9b01393
24. He, W., Wei, L., & Zou, Q. (2019). Research progress in protein posttranslational modification site prediction. Briefings in Functional Genomics, 18(4), 220–229. https://doi.org/10.1093/bfgp/ely039
25. He, Y., Khan, S., Huo, Z., Lv, D., Zhang, X., Liu, X., Yuan, Y., Hromas, R., Xu, M., Zheng, G., & Zhou, D. (2020). Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies. Journal of Hematology and Oncology, 13(1), 1–24. https://doi.org/10.1186/s13045-020-00924-z
26. Helgason, Á. R., Adolfsson, J., Dickman, P., Fredrikson, M., & Steineck, G. (1998). Distress due to unwanted side-effects of prostate cancer treatment is related to impaired well-being (quality of life). Prostate Cancer and Prostatic Diseases, 1(3), 128–133. https://doi.org/10.1038/sj.pcan.4500226
27. Hu, J., Hu, B., Wang, M., Xu, F., Miao, B., Yang, C. Y., Wang, M., Liu, Z., Hayes, D. F., Chinnaswamy, K., Delproposto, J., Stuckey, J., & Wang, S. (2019). Discovery of ERD-308 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Estrogen Receptor (ER). Journal of Medicinal Chemistry, 62(3), 1420–1442. https://doi.org/10.1021/acs.jmedchem.8b01572
28. Hu, Z., & Crews, C. M. (2022). Recent Developments in PROTAC-Mediated Protein Degradation: From Bench to Clinic. ChemBioChem, 23(2). https://doi.org/10.1002/cbic.202100270
29. Hughes, G. R., Dudey, A. P., Hemmings, A. M., & Chantry, A. (2021). Frontiers in PROTACs. Drug Discovery Today, 26(10), 2377–2383. https://doi.org/10.1016/j.drudis.2021.04.010
30. Inuzuka, H., Liu, J., Wei, W., & Rezaeian, A.-H. (2022). PROTAC technology for the treatment of Alzheimer’s disease: advances and perspectives. Acta Materia Medica, 1(1), 24–41. https://doi.org/10.15212/amm-2021-0001
31. Ishida, T., & Ciulli, A. (2021). E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones. SLAS Discovery, 26(4), 484–502. https://doi.org/10.1177/2472555220965528
32. Jackson, A. L., & Linsley, P. S. (2010). Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nature Reviews Drug Discovery, 9(1), 57–67. https://doi.org/10.1038/nrd3010
33. Jiang, Y., Deng, Q., Zhao, H., Xie, M., Chen, L., Yin, F., Qin, X., Zheng, W., Zhao, Y., & Li, Z. (2018). Development of Stabilized Peptide-Based PROTACs against Estrogen Receptor α. ACS Chemical Biology, 13(3), 628–635. https://doi.org/10.1021/acschembio.7b00985
34. Jin, J., Wu, Y., Chen, J., Shen, Y., Zhang, L., Zhang, H., Chen, L., Yuan, H., Chen, H., Zhang, W., & Luan, X. (2020). The peptide PROTAC modality: A novel strategy for targeted protein ubiquitination. Theranostics, 10(22), 10141–10153. https://doi.org/10.7150/thno.46985
35. Juan, A., del Mar Noblejas-López, M., Arenas-Moreira, M., Alonso-Moreno, C., & Ocaña, A. (2022). Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles. Frontiers in Cell and Developmental Biology, 9(February), 1–13. https://doi.org/10.3389/fcell.2021.805336
36. Kargbo, R. B. (2019). PROTAC-Mediated Degradation of Estrogen Receptor in the Treatment of Cancer. ACS Medicinal Chemistry Letters, 10(10), 1367–1369. https://doi.org/10.1021/acsmedchemlett.9b00397
37. Khalil, R. (2018). Ubiquitin-proteasome pathway and muscle atrophy. Advances in Experimental Medicine and Biology, 1088, 235–248. https://doi.org/10.1007/978-981-13-1435-3_10
38. Klein, V. G., Townsend, C. E., Testa, A., Zengerle, M., Maniaci, C., Hughes, S. J., Chan, K. H., Ciulli, A., & Lokey, R. S. (2020). Understanding and Improving the Membrane Permeability of VH032-Based PROTACs. ACS Medicinal Chemistry Letters, 11(9), 1732–1738. https://doi.org/10.1021/acsmedchemlett.0c00265
39. Langley, D. R., & Crews, C. M. (2022). PROTAC targeted protein degraders: the past is prologue. 21(March). https://doi.org/10.1038/s41573-021-00371-6
40. Li, H., Dong, J., Cai, M., Xu, Z., Cheng, X. D., & Qin, J. J. (2021). Protein degradation technology: a strategic paradigm shift in drug discovery. Journal of Hematology and Oncology, 14(1), 1–23. https://doi.org/10.1186/s13045-021-01146-7
41. Li, Liang, Mi, D., Pei, H., Duan, Q., Wang, X., Zhou, W., Jin, J., Li, D., Liu, M., & Chen, Y. (2020). In vivo target protein degradation induced by PROTACs based on E3 ligase DCAF15. Signal Transduction and Targeted Therapy, 5(1), 4–6. https://doi.org/10.1038/s41392-020-00245-0
42. Li, Long, Zhu, X., Qian, Y., Yuan, X., Ding, Y., Hu, D., He, X., & Wu, Y. (2020). Chimeric Antigen Receptor T-Cell Therapy in Glioblastoma: Current and Future. Frontiers in Immunology, 11(November), 1–9. https://doi.org/10.3389/fimmu.2020.594271
43. Li, W., & Zhang, L. (2019). Regulation of ATG and Autophagy Initiation. In Advances in Experimental Medicine and Biology (Vol. 1206). https://doi.org/10.1007/978-981-15-0602-4_2
44. Li, Z., Ma, S., Yang, X., Zhang, L., Liang, D., Dong, G., Du, L., Lv, Z., & Li, M. (2021). Development of photocontrolled BRD4 PROTACs for tongue squamous cell carcinoma (TSCC). European Journal of Medicinal Chemistry, 222, 113608. https://doi.org/10.1016/j.ejmech.2021.113608
45. Liao, H., Li, X., Zhao, L., Wang, Y., Wang, X., Wu, Y., Zhou, X., Fu, W., Liu, L., Hu, H. G., & Chen, Y. G. (2020). A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer. Cell Discovery, 6(1), 1–12. https://doi.org/10.1038/s41421-020-0171-1
46. Lin, X., Xiang, H., & Luo, G. (2020). Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance. European Journal of Medicinal Chemistry, 206, 112689. https://doi.org/10.1016/j.ejmech.2020.112689
47. Liu, Jing, Ma, J., Liu, Y., Xia, J., Li, Y., Wang, Z. P., & Wei, W. (2020). PROTACs: A novel strategy for cancer therapy. Seminars in Cancer Biology, 67(January), 171–179. https://doi.org/10.1016/j.semcancer.2020.02.006
48. Liu, Jinyuan, Xue, L., Xu, X., Luo, J., & Zhang, S. (2021). FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer. Experimental Cell Research, 408(2), 112868. https://doi.org/10.1016/j.yexcr.2021.112868
49. Liu, L., Shi, L., Wang, Z., Zeng, J., Wang, Y., Xiao, H., & Zhu, Y. (2022). Targeting Oncoproteins for Degradation by Small Molecule-Based Proteolysis-Targeting Chimeras (PROTACs) in Sex Hormone-Dependent Cancers. Frontiers in Endocrinology, 13(March), 1–15. https://doi.org/10.3389/fendo.2022.839857
50. Liu, W. J., Ye, L., Huang, W. F., Guo, L. J., Xu, Z. G., Wu, H. L., Yang, C., & Liu, H. F. (2016). P62 Links the Autophagy Pathway and the Ubiqutin-Proteasome System Upon Ubiquitinated Protein Degradation. Cellular and Molecular Biology Letters, 21(1), 1–14. https://doi.org/10.1186/s11658-016-0031-z
51. Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., & Crews, C. M. (2015). Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chemistry and Biology, 22(6), 755–763. https://doi.org/10.1016/j.chembiol.2015.05.009
52. Lupfer, C., Thomas, P. G., Anand, P. K., Vogel, P., Milasta, S., Martinez, J., Huang, G., Green, M., Kundu, M., Chi, H., Xavier, R. J., Green, D. R., Lamkanfi, M., Dinarello, C. A., Doherty, P. C., & Kanneganti, T. D. (2013). Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nature Immunology, 14(5), 480–488. https://doi.org/10.1038/ni.2563
53. Ma, D., Zou, Y., Chu, Y., Liu, Z., Liu, G., Chu, J., Li, M., Wang, J., Sun, S. Y., & Chang, Z. (2020). A cell-permeable peptide-based PROTAC against the oncoprotein CREPT proficiently inhibits pancreatic cancer. Theranostics, 10(8), 3708–3721. https://doi.org/10.7150/thno.41677
54. Maranchie, J. K., Vasselli, J. R., Riss, J., Bonifacino, J. S., Linehan, W. M., & Klausner, R. D. (2002). The contribution of VHL substrate binding and HIF1-α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell, 1(3), 247–255. https://doi.org/10.1016/S1535-6108(02)00044-2
55. Mares, A., Miah, A. H., Smith, I. E. D., Rackham, M., Thawani, A. R., Cryan, J., Haile, P. A., Votta, B. J., Beal, A. M., Capriotti, C., Reilly, M. A., Fisher, D. T., Zinn, N., Bantscheff, M., MacDonald, T. T., Vossenkamper, A., Dace, P., Churcher, I., Benowitz, A. B., … Harling, J. D. (2020). Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Communications Biology, 3(1), 1–13. https://doi.org/10.1038/s42003-020-0868-6
56. Mariani, C. J., Vasanthakumar, A., Madzo, J., Yesilkanal, A., Bhagat, T., Yu, Y., Bhattacharyya, S., Wenger, R. H., Cohn, S. L., Nanduri, J., Verma, A., Prabhakar, N. R., & Godley, L. A. (2014). TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma. Cell Reports, 7(5), 1343–1352. https://doi.org/10.1016/j.celrep.2014.04.040
57. McCoull, W., Cheung, T., Anderson, E., Barton, P., Burgess, J., Byth, K., Cao, Q., Castaldi, M. P., Chen, H., Chiarparin, E., Carbajo, R. J., Code, E., Cowan, S., Davey, P. R., Ferguson, A. D., Fillery, S., Fuller, N. O., Gao, N., Hargreaves, D., … Wilson, D. M. (2018). Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC to Provide Insight into Small Molecule Targeting of BCL6. ACS Chemical Biology, 13(11), 3131–3141. https://doi.org/10.1021/acschembio.8b00698
58. Memon, H., & Patel, B. M. (2022). PROTACs: Novel approach for cancer breakdown by breaking proteins. Life Sciences, 300(April), 120577. https://doi.org/10.1016/j.lfs.2022.120577
59. Morán Luengo, T., Mayer, M. P., & Rüdiger, S. G. D. (2019). The Hsp70–Hsp90 Chaperone Cascade in Protein Folding. Trends in Cell Biology, 29(2), 164–177. https://doi.org/10.1016/j.tcb.2018.10.004
60. Muddassir, M., Soni, K., Sangani, C. B., Alarifi, A., Afzal, M., Abduh, N. A. Y., Duan, Y., & Bhadja, P. (2020). Bromodomain and BET family proteins as epigenetic targets in cancer therapy: Their degradation, present drugs, and possible PROTACs. RSC Advances, 11(2), 612–636. https://doi.org/10.1039/d0ra07971e
61. Nalawansha, D. A., & Crews, C. M. (2020). PROTACs: An Emerging Therapeutic Modality in Precision Medicine. Cell Chemical Biology, 27(8), 998–1014. https://doi.org/10.1016/j.chembiol.2020.07.020
62. Neklesa, T. K., Winkler, J. D., & Crews, C. M. (2017). Targeted protein degradation by PROTACs. Pharmacology and Therapeutics, 174, 138–144. https://doi.org/10.1016/j.pharmthera.2017.02.027
63. Neklesa, T., Snyder, L. B., Willard, R. R., Vitale, N., Pizzano, J., Gordon, D. A., Bookbinder, M., Macaluso, J., Dong, H., Ferraro, C., Wang, G., Wang, J., Crews, C. M., Houston, J., Crew, A. P., & Taylor, I. (2019). ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer. Journal of Clinical Oncology, 37(7_suppl), 259–259. https://doi.org/10.1200/jco.2019.37.7_suppl.259
64. Nguyen, T. T. L., Kim, J. W., Choi, H. I., Maeng, H. J., & Koo, T. S. (2022). Development of an LC-MS/MS Method for ARV-110, a PROTAC Molecule, and Applications to Pharmacokinetic Studies. Molecules, 27(6). https://doi.org/10.3390/molecules27061977
65. Ocaña, A., & Pandiella, A. (2020). Proteólisis dirigida a quimeras (PROTACs) en la terapia del cáncer. Revista de Investigación Experimental y Clínica Del Cáncer, 39(1), 2–9. https://pubmed.ncbi.nlm.nih.gov/32933565/%0Ahttps://t.ly/TJaC
66. Paiva, S. L., & Crews, C. M. (2019). Targeted protein degradation: elements of PROTAC design. Current Opinion in Chemical Biology, 50, 111–119. https://doi.org/10.1016/j.cbpa.2019.02.022
67. Park, J., Cho, J., & Song, E. J. (2020). Ubiquitin–proteasome system (UPS) as a target for anticancer treatment. Archives of Pharmacal Research, 43(11), 1144–1161. https://doi.org/10.1007/s12272-020-01281-8
68. Pietri, E., Conteduca, V., Andreis, D., Massa, I., Melegari, E., Sarti, S., Cecconetto, L., Schirone, A., Bravaccini, S., Serra, P., Fedeli, A., Maltoni, R., Amadori, D., De Giorgi, U., & Rocca, A. (2016). Androgen receptor signaling pathways as a target for breast cancer treatment. Endocrine-Related Cancer, 23(10), R485–R498. https://doi.org/10.1530/ERC-16-0190
69. Porta, C., Sabbatini, R., Procopio, G., Paglino, C., Galligioni, E., & Ortega, C. (2012). Primary resistance to tyrosine kinase inhibitors in patients with advanced renal cell carcinoma: State-of-the-science. Expert Review of Anticancer Therapy, 12(12), 1571–1577. https://doi.org/10.1586/era.12.81
70. Protein, C., Yang, H., & Landis-piwowar, K. R. (2015). NIH Public Access. April 2016. https://doi.org/10.2174/138920308784533998
71. Pu, L., Govindaraj, R. G., Lemoine, J. M., Wu, H. C., & Brylinski, M. (2019). Deepdrug3D: Classification of ligand-binding pockets in proteins with a convolutional neural network. PLoS Computational Biology, 15(2), 1–23. https://doi.org/10.1371/journal.pcbi.1006718
72. Qu, X., Liu, H., Song, X., Sun, N., Zhong, H., Qiu, X., Yang, X., & Jiang, B. (2021). Effective degradation of EGFRL858R+T790M mutant proteins by CRBN-based PROTACs through both proteosome and autophagy/lysosome degradation systems. European Journal of Medicinal Chemistry, 218, 113328. https://doi.org/10.1016/j.ejmech.2021.113328
73. Radchikov, V. F., Besarab, G. V., Sapsaleva, T. L., Baranikov, V. A., Glushenko, A. V., & Spivak, M. E. (2021). Rationing of non-degradable protein in diets for breeding steers. IOP Conference Series: Earth and Environmental Science, 848(1). https://doi.org/10.1088/1755-1315/848/1/012079
74. Raina, K., Lu, J., Qian, Y., Altieri, M., Gordon, D., Rossi, A. M. K., Wang, J., Chen, X., Dong, H., Siu, K., Winkler, J. D., Crew, A. P., Crews, C. M., & Coleman, K. G. (2016). PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(26), 7124–7129. https://doi.org/10.1073/pnas.1521738113
75. Rashighi, M., & Harris, J. E. (2017). HHS Public Access. Physiology & Behavior, 176(3), 139–148. https://doi.org/10.1016/j.ddtec.2019.01.002.PROteolysis
76. Rathod, D., Fu, Y., & Patel, K. (2019). BRD4 PROTAC as a novel therapeutic approach for the treatment of vemurafenib resistant melanoma: Preformulation studies, formulation development and in vitro evaluation. European Journal of Pharmaceutical Sciences, 138(July), 105039. https://doi.org/10.1016/j.ejps.2019.105039
77. Relini, A., Marano, N., & Gliozzi, A. (2014). Misfolding of amyloidogenic proteins and their interactions with membranes. Biomolecules, 4(1), 20–55. https://doi.org/10.3390/biom4010020
78. Roskoski, R. (2017). Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven lung cancers. Pharmacological Research, 117, 343–356. https://doi.org/10.1016/j.phrs.2017.01.007
79. Saeki, Y., Tanaka, K., Wijk, S. J. L. Van, Bienko, M., Dikic, I., Lysine, M., Besche, H. C., Goldberg, A. L., & Kim, H. T. (2012). Ubiquitin Family Modifiers and the Proteasome. Methods in Molecular Biology, 832(1), 423–432. https://doi.org/10.1007/978-1-61779-474-2
80. Sakamoto, K. M. (2010). Protacs for treatment of cancer. Pediatric Research, 67(5), 505–508. https://doi.org/10.1203/PDR.0b013e3181d35017
81. Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J. (2001). Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proceedings of the National Academy of Sciences of the United States of America, 98(15), 8554–8559. https://doi.org/10.1073/pnas.141230798
82. Sakamoto, K. M., Kim, K. B., Verma, R., Ransick, A., Stein, B., Crews, C. M., & Deshaies, R. J. (2003). Development of Protacs to target cancer-promoting proteins for ubiquitination and degradation. Molecular & Cellular Proteomics : MCP, 2(12), 1350–1358. https://doi.org/10.1074/mcp.T300009-MCP200
83. Samarasinghe, K. T. G., & Crews, C. M. (2021). Targeted protein degradation: A promise for undruggable proteins. Cell Chemical Biology, 28(7), 934–951. https://doi.org/10.1016/j.chembiol.2021.04.011
84. Savvidou, M. G., Katsabea, A., Kotidis, P., Mamma, D., Lymperopoulou, T. V., Kekos, D., & Kolisis, F. N. (2018). Studies on the catalytic behavior of a membrane-bound lipolytic enzyme from the microalgae Nannochloropsis oceanica CCMP1779. Enzyme and Microbial Technology, 116, 64–71. https://doi.org/10.1016/j.enzmictec.2018.05.011
85. Schneekloth, J. S., Fonseca, F. N., Koldobskiy, M., Mandal, A., Deshaies, R., Sakamoto, K., & Crews, C. M. (2004). Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation. Journal of the American Chemical Society, 126(12), 3748–3754. https://doi.org/10.1021/ja039025z
86. Song M, Emilsson L, Bozorg SR, Nguyen LH, Joshi AD, Staller K, et al. (2020). HHS Public Access. Lancet Gastroenterol Hepatol, 5(6), 537–547. https://doi.org/10.1080/17460441.2019.1659242.PROTACs
87. Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y., Tong, Y., & Rao, Y. (2019). Protacs: Great opportunities for academia and industry. Signal Transduction and Targeted Therapy, 4(1). https://doi.org/10.1038/s41392-019-0101-6
88. Sun, Y., Zhao, X., Ding, N., Gao, H., Wu, Y., Yang, Y., Zhao, M., Hwang, J., Song, Y., Liu, W., & Rao, Y. (2018). PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Research, 28(7), 779–781. https://doi.org/10.1038/s41422-018-0055-1
89. Tang, K., Jia, Y. N., Yu, B., & Liu, H. M. (2020). Medicinal chemistry strategies for the development of protein tyrosine phosphatase SHP2 inhibitors and PROTAC degraders. European Journal of Medicinal Chemistry, 204, 112657. https://doi.org/10.1016/j.ejmech.2020.112657
90. Tinworth, C. P., Lithgow, H., Dittus, L., Bassi, Z. I., Hughes, S. E., Muelbaier, M., Dai, H., Smith, I. E. D., Kerr, W. J., Burley, G. A., Bantscheff, M., & Harling, J. D. (2019). PROTAC-Mediated Degradation of Bruton’s Tyrosine Kinase Is Inhibited by Covalent Binding. ACS Chemical Biology, 14(3), 342–347. https://doi.org/10.1021/acschembio.8b01094
91. Toure, M., & Crews, C. M. (2016). Small-molecule PROTACS: New approaches to protein degradation. Angewandte Chemie - International Edition, 55(6), 1966–1973. https://doi.org/10.1002/anie.201507978
92. Wang, C., Zheng, C., Wang, H., Zhang, L., Liu, Z., & Xu, P. (2022). The state of the art of PROTAC technologies for drug discovery. European Journal of Medicinal Chemistry, 235, 114290. https://doi.org/10.1016/j.ejmech.2022.114290
93. Wang, P., & Zhou, J. (2018). Proteolysis Targeting Chimera (PROTAC): A Paradigm-Shifting Approach in Small Molecule Drug Discovery. Current Topics in Medicinal Chemistry, 18(16), 1354–1356. https://doi.org/10.2174/1568026618666181010101922
94. Wang, Y., Jiang, X., Feng, F., Liu, W., & Sun, H. (2020). Degradation of proteins by PROTACs and other strategies. Acta Pharmaceutica Sinica B, 10(2), 207–238. https://doi.org/10.1016/j.apsb.2019.08.001
95. Weng, G., Li, D., Kang, Y., & Hou, T. (2021). Integrative Modeling of PROTAC-Mediated Ternary Complexes. Journal of Medicinal Chemistry, 64(21), 16271–16281. https://doi.org/10.1021/acs.jmedchem.1c01576
96. Xia, L., Liu, W., Song, Y., Zhu, H., & Duan, Y. (2019). The Present and Future of Novel Protein Degradation Technology. Current Topics in Medicinal Chemistry, 19(20), 1784–1788. https://doi.org/10.2174/1568026619666191011162955
97. Xia, M., Knezevic, D., Tovar, C., Huang, B., Heimbrook, D. C., & Vassilev, L. T. (2008). Elevated MDM2 boosts the apoptotic activity of p53-MDM2 binding inhibitors by facilitating MDMX degradation. Cell Cycle, 7(11), 1604–1612. https://doi.org/10.4161/cc.7.11.5929
98. Yalçın, A. (2012). Posttranslasyonel Modifikasyon ve Protein Fonksiyonu Giriş. Uludag Univ. J Fac. Vet. Ned., 31(1), 29–37. Yang, Y., Gao, H., Sun, X., Sun, Y., Qiu, Y., Weng, Q., & Rao, Y. (2020). Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects. Journal of Medicinal Chemistry, 63(15), 8567–8583. https://doi.org/10.1021/acs.jmedchem.0c00967
99. Zeng, S., Huang, W., Zheng, X., Liyan cheng, Zhang, Z., Wang, J., & Shen, Z. (2021). Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges. European Journal of Medicinal Chemistry, 210, 112981. https://doi.org/10.1016/j.ejmech.2020.112981
100. Zhang. (2004). Targeted Degradation of Proteins by Small Molecules: A Novel Tool for Functional Proteomics†. Combinatorial Chemistry & High Throughput Screening, 7(7), 689–697. https://doi.org/10.2174/1386207043328364 Zhang, H., Zhao, H. Y., Xi, X. X., Liu, Y. J., Xin, M., Mao, S., Zhang, J. J., Lu, A. X., & Zhang, S. Q. (2020). Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC). European Journal of Medicinal Chemistry, 189, 112061. https://doi.org/10.1016/j.ejmech.2020.112061
101. Zhao, L., Han, X., Lu, J., McEachern, D., & Wang, S. (2020). A highly potent PROTAC androgen receptor (AR) degrader ARD-61 effectively inhibits AR-positive breast cancer cell growth in vitro and tumor growth in vivo. Neoplasia (United States), 22(10), 522–532. https://doi.org/10.1016/j.neo.2020.07.002
102. Zhou, P., Bogacki, R., McReynolds, L., & Howley, P. M. (2000). Harnessing the ubiquitination machinery to target the degradation of specific cellular proteins. Molecular Cell, 6(3), 751–756. https://doi.org/10.1016/S1097-2765(00)00074-5
103. Zhou, X., Dong, R., Zhang, J. Y., Zheng, X., & Sun, L. P. (2020). PROTAC: A promising technology for cancer treatment. European Journal of Medicinal Chemistry, 203, 112539. https://doi.org/10.1016/j.ejmech.2020.112539
104. Zhuang, J. jing, Liu, Q., Wu, D. lei, & Tie, L. (2022). Current strategies and progress for targeting the “undruggable” transcription factors. Acta Pharmacologica Sinica, December 2021, 1–8. https://doi.org/10.1038/s41401-021-00852-9 Zou, Y., Ma, D., & Wang, Y. (2019). The PROTAC technology in drug development. Cell Biochemistry and Function, 37(1), 21–30. https://doi.org/10.1002/cbf.3369 20050415 053. (2004).