Scilight Press

Author Information

Received: 18 May 2024 | Revised: 09 Jul 2024 | Accepted: 09 Jul 2024 | Published: 26 Aug 2024

Abstract

Keywords

PROTAC | proteolysis | protein degradation | drug discovery

References 

• 1.
  Burslem, G.M.; Crews, C.M. Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell 2020, 181, 102–114.
• 2.
  Liu, Z.; Hu, M.; Yang, Y.; et al. An overview of PROTACs: A promising drug discovery paradigm., Mol. Biomed. 2022, 3, 46.
• 3.
  Békés, M.; Langley, D.R.; Crews, C.M. PROTAC targeted protein degraders: THE past is prologue, Nat. Rev. Drug Discov. 2022, 21, 181–200.
• 4.
  Ciechanover, A. Proteolysis: FROM the lysosome to ubiquitin and the proteasome. Nat. Rev. Mol. Cell Biol. 2005, 6, 79–87.
• 5.
  Zhao, L.; Zhao, J.; Zhong, K.; et al. Targeted protein degradation: Mechanisms, strategies and application. Signal Transduct. Target. Ther. 2022, 7, 113.
• 6.
  Sha, Z.; Zhao, J.; Goldberg, A.L. Measuring the Overall Rate of Protein Breakdown in Cells and the Contributions of the Ubiquitin-Proteasome and Autophagy-Lysosomal Pathways. Methods Mol. Biol. 2018, 1844, 261–276.
• 7.
  Bard, J.A.M.; Goodall, E.A.; Greene, E.R.; et al. Structure and Function of the 26S Proteasome. Annu. Rev. Biochem. 2018, 87, 697–724.
• 8.
  Bhole, R.P.; Kute, P.R.; Chikhale, R.V.; et al. Unlocking the potential of PROTACs: A comprehensive review of protein degradation strategies in disease therapy. Bioorg. Chem. 2023, 139, 106720.
• 9.
  Middleton, A.J.; Day, C.L. The molecular basis of lysine 48 ubiquitin chain synthesis by Ube2K. Sci. Rep. 2015, 5, 16793.
• 10.
  Snyder, N.A.; Silva, G.M. Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response. J. Biol. Chem. 2021, 297, 101077.
• 11.
  Liu, X.; Ciulli, A. DUB be good to me. Nat. Chem. Biol. 2022, 18, 358–359.
• 12.
  Zhang, X.; Linder, S.; Bazzaro, M. Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers. Cancers 2020, 12, 902.
• 13.
  Li, D.; Yu, D.; Li, Y.; et al. A bibliometric analysis of PROTAC from 2001 to 2021. Eur. J. Med. Chem. 2022, 244, 114838.
• 14.
  Martín-Acosta, P.; Xiao, X. PROTACs to address the challenges facing small molecule inhibitors. Eur. J. Med. Chem. 2021, 210, 112993.
• 15.
  Bondeson, D.P.; Smith, B.E.; Burslem, G.M.; et al. Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead, Cell Chem. Biol. 2018, 25, 78–87.
• 16.
  Zagidullin, A.; Milyukov, V.; Rizvanov, A.; et al. Novel approaches for the rational design of PROTAC linkers, Explor. Target. Anti-tumor Ther. 2020, 1, 381–390.
• 17.
  Bricelj, A.; Steinebach, C.; Kuchta, R.; et al. E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points. Front. Chem. 2021, 9, 707317.
• 18.
  Hendrick, C.E.; Jorgensen, J.R.; Chaudhry, C.; et al. Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation. ACS Med. Chem. Lett. 2022, 13, 1182–1190.
• 19.
  Sakamoto, K.M.; Kim, K.B.; Kumagai, A.; et al. Deshaies, Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 2001, 98, 8554–8559.
• 20.
  Schneekloth, J.S.; Fonseca, F.N.; Koldobskiy, M.; et al. Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation. J. Am. Chem. Soc., 2004, 126, 3748–3754.
• 21.
  Schneekloth, A.R.; Pucheault, M.; Tae, H.S.; et al. Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics. Bioorg. Med. Chem. Lett. 2008, 18, 5904–5908.
• 22.
  Zheng, N.; Shabek, N. Ubiquitin Ligases: Structure, Function, and Regulation. Annu. Rev. Biochem. 2017, 86, 129–157.
• 23.
  Itoh, Y.; Ishikawa, M.; Naito, M.; et al. Protein knockdown using methyl bestatin-ligand hybrid molecules: Design and synthesis of inducers of ubiquitination-mediated degradation of cellular retinoic acid-binding proteins. J. Am. Chem. Soc. 2010, 132, 5820–5826.
• 24.
  Lu, J.; Qian, Y.; Altieri, M.; et al. Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. Chem. Biol. 2015, 22, 755–763.
• 25.
  Setia, N.; Almuqdadi, H.T.A.; Abid, M. Journey of Von Hippel-Lindau (VHL) E3 ligase in PROTACs design: From VHL ligands to VHL-based degraders. Eur. J. Med. Chem. 2024, 265, 116041.
• 26.
  Zhang, X.; Crowley, V.M.; Wucherpfennig, T.G.; et al. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat. Chem. Biol. 2019, 15, 737–746.
• 27.
  Han, T.; Goralski, M.; Gaskill, N.; et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 2017, 356, eaal3755.
• 28.
  Lu, M.; Liu, T.; Jiao, Q.; et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination-proteasome degradation pathway. Eur. J. Med. Chem. 2018, 146, 251–259.
• 29.
  Luo, M.; Spradlin, J.N.; Boike, L.; et al. Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function. Cell Chem. Biol. 2021, 28, 559–566.e15.
• 30.
  Chen, S.; Li, X.; Li, Y.; et al. Design of stapled peptide-based PROTACs for MDM2/MDMX atypical degradation and tumor suppression. Theranostics 2022, 12, 6665–6681.
• 31.
  Adhikari, B.; Bozilovic, J.; Diebold, M.; et al. PROTAC-mediated degradation reveals a non-catalytic function of AURORA-A kinase., Nat. Chem. Biol. 2020, 16, 1179–1188.
• 32.
  Chirnomas, D.; Hornberger, K.R.; Crews, C.M. Protein degraders enter the clinic—A new approach to cancer therapy. Nat. Rev. Clin. Oncol. 2023, 20, 265–278.
• 33.
  Yang, W.; Saboo, S.; Zhou, L.; et al. Early evaluation of opportunities in oral delivery of PROTACs to overcome their molecular challenges. Drug Discov. Today 2024, 29, 103865.
• 34.
  Conde, J.; Artzi, N. Are RNAi and miRNA therapeutics truly dead? Trends Biotechnol. 2015, 33, 141–144.
• 35.
  Lazo, J.S.; Sharlow, E.R. Drugging Undruggable Molecular Cancer Targets. Annu. Rev. Pharmacol. Toxicol. 2016, 56, 23––40.
• 36.
  Li, X.; Song, Y. Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. J. Hematol. Oncol. 2020, 13, 50.
• 37.
  Han, X.; Zhao, L.; Xiang, W.; et al. Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands. J. Med. Chem. 2019, 62, 11218–11231.
• 38.
  Testa, A.; Lucas, X.; Castro, G.V.; et al. Fletcher and A. Ciulli, 3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation, J. Am. Chem. Soc. 2018, 140, 9299–9313.
• 39.
  Lee, J.; Lee, Y.; Jung, Y.M.; et al. Discovery of E3 Ligase Ligands for Target Protein Degradation. Molecules 2022, 27, 6515.
• 40.
  Zeng, S.; Huang, W.; Zheng, X.; et al. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges. Eur. J. Med. Chem. 2021, 210, 112981.
• 41.
  Smith, B.E.; Wang, S.L.; Jaime-Figueroa, S.; et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat. Commun. 2019, 10, 131.
• 42.
  Smalley, J.P.; Adams, G.E.; Millard, C.J.; et al. PROTAC-mediated degradation of class I histone deacetylase enzymes in corepressor complexes. Chem. Commun. 2020, 56, 4476–4479.
• 43.
  Smalley, J.P.; Baker, I.M.; Pytel, W.A.; et al. Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells, J. Med. Chem. 2022, 65, 5642–5659.
• 44.
  Koravovic, M.; Markovic, B.; Kovacevic, M.; et al. Protein degradation induced by PROTAC molecules as an emerging drug discovery strategy. J. Serbian Chem. Soc. 2022, 87, 785–811.
• 45.
  Bondeson, D.P.; Mares, A.; Smith, I.E.D.; et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol. 2015, 11, 611–617.
• 46.
  Graham, H. The mechanism of action and clinical value of PROTACs: A graphical review. Cell. Signal. 2022, 99, 110446.
• 47.
  Sun, X.; Rao, Y. PROTACs as Potential Therapeutic Agents for Cancer Drug Resistance. Biochemistry 2020, 59, 240–249.
• 48.
  Snyder, L.B.; Neklesa, T.K.; Chen, X.; et al. Abstract 43: Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer. Cancer Res. 2021, 81, 43–43.
• 49.
  Xie, H.; Liu, J.; Alem Glison, D.M.; et al. The clinical advances of proteolysis targeting chimeras in oncology. Explor. Target. Anti-Tumor Ther. 2021, 2, 511–521.
• 50.
  Flanagan, J.; Qian, Y.; Gough, S.; et al. Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer. Cancer Res. 2019, 79, P5-04.
• 51.
  Khan, S.; Zhang, X.; Lv, D.; et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 2019, 25, 1938–1947.
• 52.
  He, Y.; Koch, R.; Budamagunta, V.; et al. DT2216—A Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas. J. Hematol. Oncol. 2020, 13, 95.
• 53.
  He, Y.; Koch, R.; Budamagunta, V.; et al. Weinstock and D. Zhou, DT2216, a BCL-XL Proteolysis Targeting Chimera (PROTAC), Is a Potent Anti T-Cell Lymphoma Agent That Does Not Induce Significant Thrombocytopenia. Blood 2019, 134, 303.
• 54.
  Robbins, D.W.; Kelly, A.; Tan, M.; et al. Nx-2127, a Degrader of BTK and IMiD Neosubstrates, for the Treatment of B-Cell Malignancies. Blood 2020, 136, 34.
• 55.
  Noviski, M.A.; Ma, J.; Lee, E.; et al. Abstract 1126: Concurrent degradation of BTK and IMiD neosubstrates by NX-2127 enhances multiple mechanisms of tumor killing. Cancer Res. 2022, 82, 1126.
• 56.
  Robbins, D.W.; Noviski, M.; Rountree, R.; et al. Nx-5948, a Selective Degrader of BTK with Activity in Preclinical Models of Hematologic and Brain Malignancies. Blood 2021, 138, 2251.
• 57.
  Chen S.-H.; Prakash, S.; Helgason, E.; et al. Constitutive protein degradation induces acute cell death via proteolysis products. bioRxiv 2023. https://doi.org/10.1101/2023.02.06.527237.
• 58.
  Chen, Q.; Liu, C.; Wang, W.; et al. Optimization of PROTAC ternary complex using DNA encoded library approach. ACS Chem. Biol. 2023, 18, 25–33.