Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Extracellular targeted protein degradation: an emerging modality for drug discovery

Nature Reviews Drug Discovery volume 23, pages 126–140 (2024)Cite this article

Subjects

Abstract

Targeted protein degradation (TPD) has emerged in the past decade as a major new drug modality to remove intracellular proteins with bispecific small molecules that recruit the protein of interest (POI) to an E3 ligase for degradation in the proteasome. Unlike classic occupancy-based drugs, intracellular TPD (iTPD) eliminates the target and works catalytically, and so can be more effective and sustained, with lower dose requirements. Recently, this approach has been expanded to the extracellular proteome, including both secreted and membrane proteins. Extracellular targeted protein degradation (eTPD) uses bispecific antibodies, conjugates or small molecules to degrade extracellular POIs by trafficking them to the lysosome for degradation. Here, we focus on recent advances in eTPD, covering degrader systems, targets, molecular designs and parameters to advance them. Now almost any protein, intracellular or extracellular, is addressable in principle with TPD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: General mechanisms for targeted protein degraders that co-opt endogenous protein degradation pathways.
Fig. 2: Six different approaches for degrading extracellular proteins.

Similar content being viewed by others

References

  1. Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

    Article  PubMed  Google Scholar 

  2. Lundstrom, K. An overview on GPCRs and drug discovery: structure-based drug design and structural biology on GPCRs. Methods Mol. Biol. 552, 51–66 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carter, P. J. & Rajpal, A. Designing antibodies as therapeutics. Cell 185, 2789–2805 (2022).

    Article  CAS  PubMed  Google Scholar 

  4. Urquhart, L. Top companies and drugs by sales in 2022. Nat. Rev. Drug. Discov. 22, 260 (2023).

    Article  CAS  PubMed  Google Scholar 

  5. Carter, P. J. & Lazar, G. A. Next generation antibody drugs: pursuit of the ‘high-hanging fruit’. Nat. Rev. Drug. Discov. 17, 197–223 (2018).

    Article  CAS  PubMed  Google Scholar 

  6. Laustsen, A. H., Greiff, V., Karatt-Vellatt, A., Muyldermans, S. & Jenkins, T. P. Animal immunization, in vitro display technologies, and machine learning for antibody discovery. Trends Biotechnol. 39, 1263–1273 (2021).

    Article  CAS  PubMed  Google Scholar 

  7. Kunert, R. & Reinhart, D. Advances in recombinant antibody manufacturing. Appl. Microbiol. Biotechnol. 100, 3451–3461 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mullard, A. FDA approves 100th monoclonal antibody product. Nat. Rev. Drug. Discov. 20, 491–495 (2021).

    Article  CAS  PubMed  Google Scholar 

  9. Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation. Proc. Natl Acad. Sci. USA 98, 8554–8559 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schreiber, S. L. The rise of molecular glues. Cell 184, 3–9 (2021).

    Article  CAS  PubMed  Google Scholar 

  11. Békés, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the past is prologue. Nat. Rev. Drug Discov. 21, 181–200 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Rousseau, A. & Bertolotti, A. Regulation of proteasome assembly and activity in health and disease. Nat. Rev. Mol. Cell Biol. 19, 697–712 (2018).

    Article  CAS  PubMed  Google Scholar 

  13. Oh, E., Akopian, D. & Rape, M. Principles of ubiquitin-dependent signaling. Annu. Rev. Cell Dev. Biol. 34, 137–162 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Duan, S. & Pagano, M. Ubiquitin ligases in cancer: functions and clinical potentials. Cell Chem. Biol. 28, 918–933 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dikic, I. & Schulman, B. A. An expanded lexicon for the ubiquitin code. Nat. Rev. Mol. Cell Biol. 24, 273–287 (2023).

    Article  CAS  PubMed  Google Scholar 

  16. Zhang, Z. et al. Role of lysosomes in physiological activities, diseases, and therapy. J. Hematol. Oncol. 14, 79 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Riching, K. M. et al. Quantitative live-cell kinetic degradation and mechanistic profiling of PROTAC mode of action. ACS Chem. Biol. 13, 2758–2770 (2018).

    Article  CAS  PubMed  Google Scholar 

  18. Kannt, A. & Đikić, I. Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation. Cell Chem. Biol. 28, 1014–1031 (2021).

    Article  CAS  PubMed  Google Scholar 

  19. Jevtić, P., Haakonsen, D. L. & Rapé, M. An E3 ligase guide to the galaxy of small-molecule-induced protein degradation. Cell Chem. Biol. 28, 1000–1013 (2021).

    Article  PubMed  Google Scholar 

  20. Poirson, J. et al. Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizers. bioRxiv 2022.08.15.503206 Preprint at https://doi.org/10.1101/2022.08.15.503206 (2022).

  21. Zhao, L., Zhao, J., Zhong, K., Tong, A. & Jia, D. Targeted protein degradation: mechanisms, strategies and application. Signal Transduct. Target. Ther. 7, 113 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lin, J. et al. Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins. Theranostics 11, 8337–8349 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pei, J. et al. Targeting lysosomal degradation pathways: new strategies and techniques for drug discovery. J. Med. Chem. 64, 3493–3507 (2021).

    Article  CAS  PubMed  Google Scholar 

  24. Dumontet, C., Reichert, J. M., Senter, P. D., Lambert, J. M. & Beck, A. Antibody–drug conjugates come of age in oncology. Nat. Rev. Drug. Discov. 22, 641–661 (2023).

    Article  CAS  PubMed  Google Scholar 

  25. Sterner, R. C. & Sterner, R. M. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 11, 69 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Goebeler, M.-E. & Bargou, R. C. T cell-engaging therapies — BiTEs and beyond. Nat. Rev. Clin. Oncol. 17, 418–434 (2020).

    Article  PubMed  Google Scholar 

  27. Crews, C. M. Targeting the undruggable proteome: the small molecules of my dreams. Chem. Biol. 17, 551–555 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jayson, G. C. et al. Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer. Eur. J. Cancer 41, 555–563 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Xiao, J. J. et al. Pharmacokinetics of anti-hepcidin monoclonal antibody Ab 12B9m and hepcidin in cynomolgus monkeys. AAPS J. 12, 646–657 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Byrd, J. C. et al. Phase 1 study of lumiliximab with detailed pharmacokinetic and pharmacodynamic measurements in patients with relapsed or refractory chronic lymphocytic leukemia. Clin. Cancer Res. 13, 4448–4455 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Clark, R. G. et al. Recombinant human growth hormone (GH)-binding protein enhances the growth-promoting activity of human GH in the rat. Endocrinology 137, 4308–4315 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Pyzik, M., Kozicky, L. K., Gandhi, A. K. & Blumberg, R. S. The therapeutic age of the neonatal Fc receptor. Nat. Rev. Immunol. 23, 415–432 (2023).

    Article  CAS  PubMed  Google Scholar 

  33. Latvala, S., Jacobsen, B., Otteneder, M. B., Herrmann, A. & Kronenberg, S. Distribution of FcRn across species and tissues. J. Histochem. Cytochem. 65, 321–333 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kuo, T. T. et al. Neonatal Fc receptor: from immunity to therapeutics. J. Clin. Immunol. 30, 777–789 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Igawa, T., Haraya, K. & Hattori, K. Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation. Immunol. Rev. 270, 132–151 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Rudenko, G. et al. Structure of the LDL receptor extracellular domain at endosomal pH. Science 298, 2353–2358 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Mircic, M. & Kavanaugh, A. The clinical efficacy of tocilizumab in rheumatoid arthritis. Drugs Today 45, 189 (2009).

    Article  Google Scholar 

  38. Rose-John, S., Scheller, J., Elson, G. & Jones, S. A. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J. Leukoc. Biol. 80, 227–236 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Igawa, T. et al. Antibody recycling by engineered pH-dependent antigen binding improves the duration of antigen neutralization. Nat. Biotechnol. 28, 1203–1207 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Deng, R. et al. Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-α antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys. Drug. Metab. Dispos. 38, 600–605 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Wang, C. et al. Investigation of endosome and lysosome biology by ultra pH-sensitive nanoprobes. Adv. Drug. Deliv. Rev. 113, 87–96 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Devanaboyina, S. C. et al. The effect of pH dependence of antibody-antigen interactions on subcellular trafficking dynamics. mAbs 5, 851–859 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Bostrom, J., Lee, C. V., Haber, L. & Fuh, G. in Dimitrov, A. S. (ed.) Therapeutic Antibodies (ed. Dimitrov, A. S.) 353–376 Methods in Molecular Biology vol. 525 (Humana Press, 2009).

  44. Igawa, T. et al. Engineered monoclonal antibody with novel antigen-sweeping activity in vivo. PLoS ONE 8, e63236 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. DRUGS. FDA approves enspryng (satralizumab-mwge) for neuromyelitis optica spectrum disorder. Drugs.com https://www.drugs.com/newdrugs/fda-approves-enspryng-satralizumab-mwge-neuromyelitis-optica-spectrum-disorder-5326.html (2020).

  46. Paton, D. M. Satralizumab: an interleukin-6 (IL-6) receptor antagonist for the treatment of neuromyelitis optica spectrum disorders. Drugs Today 57, 209 (2021).

    Article  CAS  Google Scholar 

  47. Zhang, L. et al. An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes. Int. J. Biol. Sci. 8, 310 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bonvin, P. et al. De novo isolation of antibodies with pH-dependent binding properties. mAbs 7, 294–302 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Murtaugh, M. L., Fanning, S. W., Sharma, T. M., Terry, A. M. & Horn, J. R. A combinatorial histidine scanning library approach to engineer highly pH-dependent protein switches. Protein Sci. 20, 1619–1631 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hong, S.-T., Su, Y.-C., Wang, Y.-J., Cheng, T.-L. & Wang, Y.-T. Anti-TNF alpha antibody humira with pH-dependent binding characteristics: a constant-pH molecular dynamics, gaussian accelerated molecular dynamics, and in vitro study. Biomolecules 11, 334 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Iwayanagi, Y. et al. Inhibitory FcγRIIb-mediated soluble antigen clearance from plasma by a pH-dependent antigen-binding antibody and its enhancement by Fc engineering. J. Immunol. 195, 3198–3205 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ghosh, P., Dahms, N. M. & Kornfeld, S. Mannose 6-phosphate receptors: new twists in the tale. Nat. Rev. Mol. Cell Biol. 4, 202–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Gary-Bobo, M., Nirde, P., Jeanjean, A., Morere, A. & Garcia, M. Mannose 6-phosphate receptor targeting and its applications in human diseases. Curr. Med. Chem. 14, 2945–2953 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Blanchard, F. et al. Mannose 6-phosphate/insulin-like growth factor II receptor mediates internalization and degradation of leukemia inhibitory factor but not signal transduction. J. Biol. Chem. 274, 24685–24693 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Banik, S. M. et al. Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature 584, 291–297 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vidal, S., Montero, J.-L., Leydet, A. & Morère, A. A flexible route to mannose 6-phosphonate functionalized derivatives. Phosphorus Sulfur Silicon Relat. Elem. 177, 2363–2377 (2002).

    Article  CAS  Google Scholar 

  57. Mizuno, E. et al. Regulation of epidermal growth factor receptor down-regulation by UBPY-mediated deubiquitination at endosomes. Mol. Biol. Cell 16, 5163–5174 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kiess, W. et al. Insulin-like growth factor-II (IGF-II) inhibits both the cellular uptake of β-galactosidase and the binding of β-galactosidase to purified IGF-II/mannose 6-phosphate receptor. J. Biol. Chem. 264, 4710–4714 (1989).

    Article  CAS  PubMed  Google Scholar 

  59. Ahn, G. et al. Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras. Science 382, eadf6249 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Spiess, M. The asialoglycoprotein receptor: a model for endocytic transport receptors. Biochemistry 29, 10009–10018 (1990).

    Article  CAS  PubMed  Google Scholar 

  61. D’Souza, A. A. & Devarajan, P. V. Asialoglycoprotein receptor mediated hepatocyte targeting — strategies and applications. J. Control. Release 203, 126–139 (2015).

    Article  PubMed  Google Scholar 

  62. Schwartz, A. L., Fridovich, S. E. & Lodish, H. F. Kinetics of internalization and recycling of the asialoglycoprotein receptor in a hepatoma cell line. J. Biol. Chem. 257, 4230–4237 (1982).

    Article  CAS  PubMed  Google Scholar 

  63. Tanowitz, M. et al. Asialoglycoprotein receptor 1 mediates productive uptake of N-acetylgalactosamine-conjugated and unconjugated phosphorothioate antisense oligonucleotides into liver hepatocytes. Nucleic Acids Res. 45, 12388–12400 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ahn, G. et al. LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nat. Chem. Biol. 17, 937–946 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zhou, Y., Teng, P., Montgomery, N. T., Li, X. & Tang, W. Development of triantennary N-acetylgalactosamine conjugates as degraders for extracellular proteins. ACS Cent. Sci. 7, 499–506 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Caianiello, D. F. et al. Bifunctional small molecules that mediate the degradation of extracellular proteins. Nat. Chem. Biol. 17, 947–953 (2021).

    Article  CAS  PubMed  Google Scholar 

  67. Kimura, R. H., Levin, A. M. & Cochran, J. R. Engineered cystine knot peptides that bind αvβ3, αvβ5, and α5β1 integrins with low nanomolar affinity. Proteins 77, 359–369 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cox, N., Kintzing, J. R., Smith, M., Grant, G. A. & Cochran, J. R. Integrin-targeting knottin peptide–drug conjugates are potent inhibitors of tumor cell proliferation. Angew. Chem. Int. Ed. Engl. 55, 9894–9897 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rensen, P. C. N. et al. Determination of the upper size limit for uptake and processing of ligands by the asialoglycoprotein receptor on hepatocytes in vitro and in vivo. J. Biol. Chem. 276, 37577–37584 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Douglass, E. F., Miller, C. J., Sparer, G., Shapiro, H. & Spiegel, D. A. A comprehensive mathematical model for three-body binding equilibria. J. Am. Chem. Soc. 135, 6092–6099 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Saulnier, M. et al. ASGPR-binding compounds for the degradation of extracellular proteins. World Intellect. Prop. Org. WO2021155317 (2021).

  72. Nair, J. K. et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136, 16958–16961 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Springer, A. D. & Dowdy, S. F. GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics. Nucleic Acid Ther. 28, 109–118 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wu, Y. et al. Aptamer-LYTACs for targeted degradation of extracellular and membrane proteins. Angew. Chem. Int. Ed. Engl. 62, e202218106 (2023).

    Article  CAS  PubMed  Google Scholar 

  75. Shangguan, D. et al. Aptamers evolved from live cells as effective molecular probes for cancer study. Proc. Natl Acad. Sci. USA 103, 11838–11843 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Green, L. S. et al. Inhibitory DNA ligands to platelet-derived growth factor B-chain. Biochemistry 35, 14413–14424 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. George, A. J., Hoffiz, Y. C., Charles, A. J., Zhu, Y. & Mabb, A. M. A comprehensive atlas of E3 ubiquitin ligase mutations in neurological disorders. Front. Genet. 9, 29 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Nakamura, N. The role of the transmembrane RING finger proteins in cellular and organelle function. Membranes 1, 354–393 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Cotton, A. D., Nguyen, D. P., Gramespacher, J. A., Seiple, I. B. & Wells, J. A. Development of antibody-based PROTACs for the degradation of the cell-surface immune checkpoint protein PD-L1. J. Am. Chem. Soc. 143, 593–598 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zebisch, M. et al. Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nat. Commun. 4, 2787 (2013).

    Article  PubMed  Google Scholar 

  81. Zhang, F. et al. Structural basis of the therapeutic anti-PD-L1 antibody atezolizumab. Oncotarget 8, 90215–90224 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Gramespacher, J. A., Cotton, A. D., Burroughs, P. W. W., Seiple, I. B. & Wells, J. A. Roadmap for optimizing and broadening antibody-based PROTACs for degradation of cell surface proteins. ACS Chem. Biol. 17, 1259–1268 (2022).

    Article  CAS  PubMed  Google Scholar 

  83. Hao, H.-X. et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485, 195–200 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Papatheodorou, I. et al. Expression atlas update: from tissues to single cells. Nucleic Acids Res. 48, D77–D83 (2020).

    CAS  PubMed  Google Scholar 

  85. Marei, H. et al. Antibody targeting of E3 ubiquitin ligases for receptor degradation. Nature 610, 182–189 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Arcaro, A. Targeting the insulin-like growth factor-1 receptor in human cancer. Front. Pharmacol. 4, 30 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Rowinsky, E. K. et al. Blockade of insulin-like growth factor type-1 receptor with cixutumumab (IMC-A12): a novel approach to treatment for multiple cancers. Curr. Drug Targets 12, 2016–2033 (2011).

    Article  Google Scholar 

  88. Siepe, D. H., Picton, L. K. & Garcia, K. C. Receptor elimination by E3 ubiquitin ligase recruitment (REULR): a targeted protein degradation toolbox. ACS Synth. Biol. 12, 1081–1093 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. McMahon, C. et al. Yeast surface display platform for rapid discovery of conformationally selective nanobodies. Nat. Struct. Mol. Biol. 25, 289–296 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hornbeck, P. V. et al. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 43, D512–D520 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Pance, K. et al. Modular cytokine receptor-targeting chimeras for targeted degradation of cell surface and extracellular proteins. Nat. Biotechnol. 41, 273–281 (2023).

    Article  CAS  PubMed  Google Scholar 

  92. Janssens, R., Struyf, S. & Proost, P. The unique structural and functional features of CXCL12. Cell. Mol. Immunol. 15, 299–311 (2018).

    Article  CAS  PubMed  Google Scholar 

  93. Costantini, S., Raucci, R., De Vero, T., Castello, G. & Colonna, G. Common structural interactions between the receptors CXCR3, CXCR4 and CXCR7 complexed with their natural ligands, CXCL11 and CXCL12, by a modeling approach. Cytokine 64, 316–321 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Stephens, B. S., Ngo, T., Kufareva, I. & Handel, T. M. Functional anatomy of the full-length CXCR4-CXCL12 complex systematically dissected by quantitative model-guided mutagenesis. Sci. Signal. 13, eaay5024 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hao, Y., Yu, X., Bai, Y., McBride, H. J. & Huang, X. Cryo-EM structure of HER2-trastuzumab-pertuzumab complex. PLoS ONE 14, e0216095 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Danhier, F., Le Breton, A. & Préat, V. RGD-based strategies to target alpha(v) beta(3) integrin in cancer therapy and diagnosis. Mol. Pharm. 9, 2961–2973 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Zheng, J. et al. Bifunctional compounds as molecular degraders for integrin-facilitated targeted protein degradation. J. Am. Chem. Soc. 144, 21831–21836 (2022).

    Article  CAS  PubMed  Google Scholar 

  98. Moreno-Layseca, P., Icha, J., Hamidi, H. & Ivaska, J. Integrin trafficking in cells and tissues. Nat. Cell Biol. 21, 122–132 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yeung, K. et al. Compounds useful as immunomodulators. US Patent 10,882,844 (2021).

  100. Brodbeck, J. et al. Structure-dependent impairment of intracellular apolipoprotein E4 trafficking and its detrimental effects are rescued by small-molecule structure correctors. J. Biol. Chem. 286, 17217–17226 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Yu, F., Cai, M., Shao, L. & Zhang, J. Targeting protein kinases degradation by PROTACs. Front. Chem. 9, 679120 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Burslem, G. M. et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem. Biol. 25, 67–77.e3 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. Konecny, G. E. et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 66, 1630–1639 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Graves, L. M., Duncan, J. S., Whittle, M. C. & Johnson, G. L. The dynamic nature of the kinome. Biochem. J. 450, 1–8 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Herbst, R. S., Fukuoka, M. & Baselga, J. Gefitinib — a novel targeted approach to treating cancer. Nat. Rev. Cancer 4, 956–965 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Cheng, M. et al. Discovery of potent and selective epidermal growth factor receptor (EGFR) bifunctional small-molecule degraders. J. Med. Chem. 63, 1216–1232 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Clift, D., So, C., McEwan, W. A., James, L. C. & Schuh, M. Acute and rapid degradation of endogenous proteins by trim-away. Nat. Protoc. 13, 2149–2175 (2018).

    Article  CAS  PubMed  Google Scholar 

  108. Lim, S. et al. bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA). Proc. Natl Acad. Sci. USA 117, 5791–5800 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shen, F. et al. A cell-permeant nanobody-based degrader that induces fetal hemoglobin. ACS Cent. Sci. 8, 1695–1703 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Pedram, K. et al. Design of a mucin-selective protease for targeted degradation of cancer-associated mucins. Nat. Biotechnol., https://doi.org/10.1038/s41587-023-01840-6 (2023).

    Article  PubMed  Google Scholar 

  111. Mayes, P. A., Hance, K. W. & Hoos, A. The promise and challenges of immune agonist antibody development in cancer. Nat. Rev. Drug. Discov. 17, 509–527 (2018).

    Article  CAS  PubMed  Google Scholar 

  112. Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Zahavi, D., AlDeghaither, D., O’Connell, A. & Weiner, L. M. Enhancing antibody-dependent cell-mediated cytotoxicity: a strategy for improving antibody-based immunotherapy. Antib. Ther. 1, 7–12 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Baeuerle, P. A. & Reinhardt, C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 69, 4941–4944 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Demaria, O., Gauthier, L., Debroas, G. & Vivier, E. Natural killer cell engagers in cancer immunotherapy: next generation of immuno-oncology treatments. Eur. J. Immunol. 51, 1934–1942 (2021).

    Article  CAS  PubMed  Google Scholar 

  116. Kingwell, K. CAR T therapies drive into new terrain. Nat. Rev. Drug. Discov. 16, 301–304 (2017).

    Article  CAS  PubMed  Google Scholar 

  117. James, L. C., Keeble, A. H., Khan, Z., Rhodes, D. A. & Trowsdale, J. Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc. Natl Acad. Sci. USA 104, 6200–6205 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Mallery, D. L. et al. Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc. Natl Acad. Sci. USA 107, 19985–19990 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ibrahim, A. F. M. et al. Antibody RING-mediated destruction of endogenous proteins. Mol. Cell 79, 155–166.e9 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sankaran, V. G. et al. Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 322, 1839–1842 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Orkin, S. H. Molecular medicine: found in translation. Med. 2, 122–136 (2021).

    Article  CAS  PubMed  Google Scholar 

  122. Melton, R. G. & Sherwood, R. F. Antibody-enzyme conjugates for cancer therapy. J. Natl Cancer Inst. 88, 153–165 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Smith, B. A. H. & Bertozzi, C. R. The clinical impact of glycobiology: targeting selectins, siglecs and mammalian glycans. Nat. Rev. Drug. Discov. 20, 217–243 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Pruszynski, M. et al. Targeting breast carcinoma with radioiodinated anti-HER2 nanobody. Nucl. Med. Biol. 40, 52–59 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Research in J.A.W.’s laboratory is funded by grants from the NIH (R35GM122451) and NCI (R01CA248323). K.K. acknowledges a graduate fellowship funded by the National Science Foundation. We also thank members of the Wells laboratory, EpiBiologics, and M. Kavanaugh for pre-reading of the manuscript. 

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA

    James A. Wells & Kaan Kumru

  2. Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA

    James A. Wells

Authors
  1. James A. Wells
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaan Kumru
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.A.W. and K.K. contributed to all aspects of the article.

Corresponding author

Correspondence to James A. Wells.

Ethics declarations

Competing interests

J.A.W. is a founder of EpiBiologics and K.K is a founding advisor.  Both hold stock in the company.

Peer review

Peer review information

Nature Reviews Drug Discovery thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

C4 Therapeutics Announces FDA Clearance of Investigational New Drug Application for CFT8919, an Orally Bioavailable BiDACTM Degrader Targeting EGFR L858R for Non-Small Cell Lung Cancer: https://ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-announces-fda-clearance-investigational-new-0/

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wells, J.A., Kumru, K. Extracellular targeted protein degradation: an emerging modality for drug discovery. Nat Rev Drug Discov 23, 126–140 (2024). https://doi.org/10.1038/s41573-023-00833-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41573-023-00833-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research