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.

  • Perspective
  • Published:

Delivering on the promise of protein degraders

Nature Reviews Drug Discovery volume 22, pages 410–427 (2023)Cite this article

Subjects

Abstract

Over the past 3 years, the first bivalent protein degraders intentionally designed for targeted protein degradation (TPD) have advanced to clinical trials, with an initial focus on established targets. Most of these clinical candidates are designed for oral administration, and many discovery efforts appear to be similarly focused. As we look towards the future, we propose that an oral-centric discovery paradigm will overly constrain the chemical designs that are considered and limit the potential to drug novel targets. In this Perspective, we summarize the current state of the bivalent degrader modality and propose three categories of degrader designs, based on their likely route of administration and requirement for drug delivery technologies. We then describe a vision for how parenteral drug delivery, implemented early in research and supported by pharmacokinetic–pharmacodynamic modelling, can enable exploration of a broader drug design space, expand the scope of accessible targets and deliver on the promise of protein degraders as a therapeutic modality.

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: A typical drug discovery paradigm for degraders.
Fig. 2: Degrader categorization to inform administration and delivery needs.
Fig. 3: Pharmacokinetic–pharmacodynamic considerations for parenterally administered degraders.
Fig. 4: Parenteral drug delivery technologies for degrader delivery.

Similar content being viewed by others

References

  1. Hopkins, A. L. & Groom, C. R. The druggable genome. Nat. Rev. Drug Discov. 1, 727–730 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  3. Churcher, I. Protac-induced protein degradation in drug discovery: breaking the rules or just making new ones? J. Med. Chem. 61, 444–452 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. Maple, H. J., Clayden, N., Baron, A., Stacey, C. & Felix, R. Developing degraders: principles and perspectives on design and chemical space. MedChemComm 10, 1755–1764 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Pettersson, M. & Crews, C. M. Proteolysis targeting chimeras (PROTACs) — past, present and future. Drug Discov. Today Technol. 31, 15–27 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug Discov. 18, 949–963 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Rambacher, K. M., Calabrese, M. F. & Yamaguchi, M. Perspectives on the development of first-in-class protein degraders. Future Med. Chem. 13, 1203–1226 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Alabi, S. B. & Crews, C. M. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. J. Biol. Chem. 296, 100647 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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 

  10. 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 

  11. Okuhira, K. et al. Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein. FEBS Lett. 585, 1147–1152 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. 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 

  13. 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 

  14. 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 

  15. Samarasinghe, K. T. G. et al. Targeted degradation of transcription factors by TRAFTACs: TRAnscription Factor TArgeting Chimeras. Cell Chem. Biol. 28, 648–661 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bondeson, D. P. et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem. Biol. 25, 78–87.e5 (2018).

    Article  CAS  PubMed  Google Scholar 

  17. Gadd, M. S. et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13, 514–521 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cantrill, C. et al. Fundamental aspects of DMPK optimization of targeted protein degraders. Drug. Discov. Today 25, 969–982 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Liu, X. et al. Assays and technologies for developing proteolysis targeting chimera degraders. Future Med. Chem. 12, 1155–1179 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Pike, A., Williamson, B., Harlfinger, S., Martin, S. & McGinnity, D. F. Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective. Drug Discov. Today 25, 1793–1800 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Rodriguez-Rivera, F. P. & Levi, S. M. Unifying catalysis framework to dissect proteasomal degradation paradigms. ACS Cent. Sci. 7, 1117–1125 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Farnaby, W. et al. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat. Chem. Biol. 15, 672–680 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Iconomou, M. & Saunders, D. N. Systematic approaches to identify E3 ligase substrates. Biochemical J. 473, 4083–4101 (2016).

    Article  CAS  Google Scholar 

  24. Khan, S. et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25, 1938–1947 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Troup, R. I., Fallan, C. & Baud, M. G. J. Current strategies for the design of PROTAC linkers: a critical review. Explor. Target. Antitumor Ther. 1, 273–312 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Morgan, P. et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug Discov. Today 17, 419–424 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Bartlett, D. W. & Gilbert, A. M. A kinetic proofreading model for bispecific protein degraders. J. Pharmacokinet. Pharmacodyn. 48, 149–163 (2021).

    Article  CAS  PubMed  Google Scholar 

  28. Bartlett, D. W. & Gilbert, A. M. Translational PK–PD for targeted protein degradation. Chem. Soc. Rev. 51, 3477–3486 (2022).

    Article  CAS  PubMed  Google Scholar 

  29. Nowak, R. P. & Jones, L. H. Target validation using PROTACs: applying the four pillars framework. SLAS Discov. 26, 474–483 (2021).

    Article  CAS  PubMed  Google Scholar 

  30. Edmondson, S. D., Yang, B. & Fallan, C. Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: recent progress and future challenges. Bioorg. Med. Chem. Lett. 29, 1555–1564 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Shultz, M. D. Two decades under the influence of the rule of five and the changing properties of approved oral drugs. J. Med. Chem. 62, 1701–1714 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Ermondi, G., Vallaro, M. & Caron, G. Degraders early developability assessment: face-to-face with molecular properties. Drug Discov. Today 25, 1585–1591 (2020).

    Article  CAS  PubMed  Google Scholar 

  33. Ermondi, G., Vallaro, M., Goetz, G., Shalaeva, M. & Caron, G. Updating the portfolio of physicochemical descriptors related to permeability in the beyond the Rule of 5 chemical space. Eur. J. Pharm. Sci. 146, 105274 (2020).

    Article  CAS  PubMed  Google Scholar 

  34. Rossi Sebastiano, M. et al. Impact of dynamically exposed polarity on permeability and solubility of chameleonic drugs beyond the Rule of 5. J. Med. Chem. 61, 4189–4202 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Klein, V. G. et al. Understanding and improving the membrane permeability of VH032-based PROTACs. ACS Med. Chem. Lett. 11, 1732–1738 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Atilaw, Y. et al. Solution conformations shed light on PROTAC cell permeability. ACS Med. Chem. Lett. 12, 107–114 (2021).

    Article  CAS  PubMed  Google Scholar 

  37. Kofink, C. et al. A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Nat. Commun. 13, 5969 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Petrylak, D. P. et al. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI). J. Clin. Oncol. https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.3500 (2020).

  39. Jin, J. et al. The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination. Theranostics 10, 10141–10153 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jiang, Y. et al. Development of stabilized peptide-based PROTACs against estrogen receptor α. ACS Chem. Biol. 13, 628–635 (2018).

    Article  CAS  PubMed  Google Scholar 

  41. Lu, M. et al. Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiquitination–proteasome degradation pathway. Eur. J. Med. Chem. 146, 251–259 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Qu, J. et al. Specific knockdown of α-synuclein by peptide-directed proteasome degradation rescued its associated neurotoxicity. Cell Chem. Biol. 27, 751–762 (2020).

    Article  CAS  PubMed  Google Scholar 

  43. Testa, A., Hughes, S. J., Lucas, X., Wright, J. E. & Ciulli, A. Structure-based design of a macrocyclic PROTAC. Angew. Chem. Int. Ed. 59, 1727–1734 (2020).

    Article  CAS  Google Scholar 

  44. Fulcher, L. J. et al. An affinity-directed protein missile system for targeted proteolysis. Open Biol. 6, 160255 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Röth, S. et al. Targeting endogenous K-RAS for degradation through the affinity-directed protein missile system. Cell Chem. Biol. 27, 1151–1163 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Simpson, L. M. et al. Inducible degradation of target proteins through a tractable affinity-directed protein missile system. Cell Chem. Biol. 27, 1164–1180 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Caussinus, E., Kanca, O. & Affolter, M. Fluorescent fusion protein knockout mediated by anti-GFP nanobody. Nat. Struct. Mol. Biol. 19, 117–121 (2012).

    Article  CAS  Google Scholar 

  48. Portnoff, A. D., Stephens, E. A., Varner, J. D. & DeLisa, M. P. Ubiquibodies, synthetic E3 ubiquitin ligases endowed with unnatural substrate specificity for targeted protein silencing. J. Biol. Chem. 289, 7844–7855 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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 

  50. Shao, J. et al. Destruction of DNA-binding proteins by programmable oligonucleotide PROTAC (O’PROTAC): effective targeting of LEF1 and ERG. Adv. Sci. 8, 2102555 (2021).

    Article  CAS  Google Scholar 

  51. Liu, J. et al. TF-PROTACs enable targeted degradation of transcription factors. J. Am. Chem. Soc. 143, 8902–8910 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Van den Mooter, G. The use of amorphous solid dispersions: a formulation strategy to overcome poor solubility and dissolution rate. Drug Discov. Today Technol. 9, e79–e85 (2012).

    Article  Google Scholar 

  53. Patel, V., Lalani, R., Bardoliwala, D., Ghosh, S. & Misra, A. Lipid-based oral formulation strategies for lipophilic drugs. AAPS PharmSciTech 19, 3609–3630 (2018).

    Article  CAS  PubMed  Google Scholar 

  54. Tran, P. et al. Overview of the manufacturing methods of solid dispersion technology for improving the solubility of poorly water-soluble drugs and application to anticancer drugs. Pharmaceutics 11, 132 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schittny, A., Huwyler, J. & Puchkov, M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Deliv. 27, 110–127 (2020).

    Article  CAS  PubMed  Google Scholar 

  56. Phan, T. N. Q., Le-Vinh, B., Efiana, N. A. & Bernkop-Schnürch, A. Oral self-emulsifying delivery systems for systemic administration of therapeutic proteins: science fiction? J. Drug Target. 27, 1017–1024 (2019).

    Article  CAS  PubMed  Google Scholar 

  57. McCartney, F. et al. Labrasol® is an efficacious intestinal permeation enhancer across rat intestine: ex vivo and in vivo rat studies. J. Control. Rel. 310, 115–126 (2019).

    Article  CAS  Google Scholar 

  58. Brayden, D. J., Hill, T. A., Fairlie, D. P., Maher, S. & Mrsny, R. J. Systemic delivery of peptides by the oral route: formulation and medicinal chemistry approaches. Adv. Drug Deliv. Rev. 157, 2–36 (2020).

    Article  CAS  PubMed  Google Scholar 

  59. Overgaard, R. V., Navarria, A., Ingwersen, S. H., Bækdal, T. A. & Kildemoes, R. J. Clinical pharmacokinetics of oral semaglutide: analyses of data from clinical pharmacology trials. Clin. Pharmacokinet. 60, 1335–1348 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Brayden, D. J. & Maher, S. Transient permeation enhancer® (TPE®) technology for oral delivery of octreotide: a technological evaluation. Expert. Opin. Drug Deliv. 18, 1501–1512 (2021).

    Article  PubMed  Google Scholar 

  61. Bækdal, T. A. et al. Effect of various dosing conditions on the pharmacokinetics of oral semaglutide, a human glucagon-like peptide-1 analogue in a tablet formulation. Diabetes Ther. 12, 1915–1927 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Lau, J. et al. Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J. Med. Chem. 58, 7370–7380 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Bucheit, J. D. et al. Oral semaglutide: a review of the first oral glucagon-like peptide 1 receptor agonist. Diabetes Technol. Ther. 22, 10–18 (2020).

    Article  CAS  PubMed  Google Scholar 

  64. Deng, F. & Bae, Y. H. Bile acid transporter-mediated oral drug delivery. J. Control. Rel. 327, 100–116 (2020).

    Article  CAS  Google Scholar 

  65. Maher, S., Ryan, K. B., Ahmad, T., O’Driscoll, C. M. & Brayden, D. J. in Nanostructured Biomaterials for Overcoming Biological Barriers (eds Alonso, M. J. & Csaba, N. S.) 39–62 (Royal Society of Chemistry, 2012).

  66. Abramson, A. et al. An ingestible self-orienting system for oral delivery of macromolecules. Science 363, 611–615 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dhalla, A. K. et al. A robotic pill for oral delivery of biotherapeutics: safety, tolerability, and performance in healthy subjects. Drug Deliv. Transl. Res. 12, 294–305 (2022).

    Article  CAS  PubMed  Google Scholar 

  68. Los, M. et al. Expression pattern of the von Hippel–Lindau protein in human tissues. Lab. Invest. 75, 231–238 (1996).

    CAS  PubMed  Google Scholar 

  69. Luo, X. et al. Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases. iScience 25, 103985 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yamanaka, S. et al. Thalidomide and its metabolite 5-hydroxythalidomide induce teratogenicity via the cereblon neosubstrate PLZF. EMBO J. 40, e105375 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Asatsuma-Okumura, T. et al. p63 is a cereblon substrate involved in thalidomide teratogenicity. Nat. Chem. Biol. 15, 1077–1084 (2019).

    Article  CAS  PubMed  Google Scholar 

  72. Matyskiela, M. E. et al. SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate. Nat. Chem. Biol. 14, 981–987 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, eaat0572 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Liu, X. et al. Discovery of XL01126: a potent, fast, cooperative, selective, orally bioavailable, and blood–brain barrier penetrant PROTAC degrader of leucine-rich repeat kinase 2. J. Am. Chem. Soc. 144, 16930–16952 (2022).

    Article  Google Scholar 

  75. Posternak, G. et al. Functional characterization of a PROTAC directed against BRAF mutant V600E. Nat. Chem. Biol. 16, 1170–1178 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Alabi, S. et al. Mutant-selective degradation by BRAF-targeting PROTACs. Nat. Commun. 12, 920 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kramer, L. T. & Zhang, X. Expanding the landscape of E3 ligases for targeted protein degradation. Curr. Res. Chem. Biol. 2, 100020 (2022).

    Article  CAS  Google Scholar 

  78. Leeson, P. D. et al. Target-based evaluation of “drug-like” properties and ligand efficiencies. J. Med. Chem. 64, 7210–7230 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Imaide, S. et al. Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity. Nat. Chem. Biol. 17, 1157–1167 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Riching, K. M., Caine, E. A., Urh, M. & Daniels, D. L. The importance of cellular degradation kinetics for understanding mechanisms in targeted protein degradation. Chem. Soc. Rev. 51, 6210–6221 (2022).

    Article  CAS  PubMed  Google Scholar 

  81. Riching, K. M. et al. CDK family PROTAC profiling reveals distinct kinetic responses and cell cycle–dependent degradation of CDK2. SLAS Discov. 26, 560–569 (2021).

    Article  CAS  PubMed  Google Scholar 

  82. Kaminskas, L. M., Boyd, B. J. & Porter, C. J. Dendrimer pharmacokinetics: the effect of size, structure and surface characteristics on ADME properties. Nanomedicine 6, 1063–1084 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Allen, T. M. & Cullis, P. R. Liposomal drug delivery systems: from concept to clinical applications. Adv. Drug Deliv. Rev. 65, 36–48 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Ashton, S. et al. Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo. Sci. Transl. Med. 8, 325ra317 (2016).

    Article  Google Scholar 

  85. Patterson, C. M. et al. Design and optimisation of dendrimer-conjugated Bcl-2/xL inhibitor, AZD0466, with improved therapeutic index for cancer therapy. Commun. Biol. 4, 112 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gabizon, A., Shmeeda, H. & Barenholz, Y. Pharmacokinetics of pegylated liposomal doxorubicin. Clin. Pharmacokinet. 42, 419–436 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Jiang, W., Lionberger, R. & Yu, L. X. In vitro and in vivo characterizations of PEGylated liposomal doxorubicin. Bioanalysis 3, 333–344 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Lamb, Y. N. & Scott, L. J. Liposomal irinotecan: a review in metastatic pancreatic adenocarcinoma. Drugs 77, 785–792 (2017).

    Article  CAS  PubMed  Google Scholar 

  89. Blair, H. A. Daunorubicin/cytarabine liposome: a review in acute myeloid leukaemia. Drugs 78, 1903–1910 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Sun, D., Zhou, S. & Gao, W. What went wrong with anticancer nanomedicine design and how to make it right. ACS Nano 14, 12281–12290 (2020).

    Article  CAS  PubMed  Google Scholar 

  91. Crommelin, D. J. A., van Hoogevest, P. & Storm, G. The role of liposomes in clinical nanomedicine development. What now? Now what? J. Control. Rel. 318, 256–263 (2020).

    Article  CAS  Google Scholar 

  92. Saraswat, A. et al. Nanoformulation of proteolysis targeting chimera targeting ‘undruggable’ c-Myc for the treatment of pancreatic cancer. Nanomedicine 15, 1761–1777 (2020).

    Article  CAS  PubMed  Google Scholar 

  93. Donahue, N. D., Acar, H. & Wilhelm, S. Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine. Adv. Drug Deliv. Rev. 143, 68–96 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Dragovich, P. S. Degrader–antibody conjugates. Chem. Soc. Rev. 51, 3886–3897 (2022).

    Article  CAS  PubMed  Google Scholar 

  95. Chari, R. V. J., Miller, M. L. & Widdison, W. C. Antibody–drug conjugates: an emerging concept in cancer therapy. Angew. Chem. Int. Ed. 53, 3796–3827 (2014).

    Article  CAS  Google Scholar 

  96. Beck, A., Goetsch, L., Dumontet, C. & Corvaïa, N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat. Rev. Drug Discov. 16, 315–337 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Sau, S., Alsaab, H. O., Kashaw, S. K., Tatiparti, K. & Iyer, A. K. Advances in antibody–drug conjugates: a new era of targeted cancer therapy. Drug Discov. Today 22, 1547–1556 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dragovich, P. S. et al. Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor α (ERα). Bioorg. Med. Chem. Lett. 30, 126907 (2020).

    Article  CAS  PubMed  Google Scholar 

  99. Pillow, T. H. et al. Antibody conjugation of a chimeric BET degrader enables in vivo activity. ChemMedChem 15, 17–25 (2020).

    Article  CAS  PubMed  Google Scholar 

  100. Dragovich, P. S. et al. Antibody-mediated delivery of chimeric BRD4 degraders. Part 1: exploration of antibody linker, payload loading, and payload molecular properties. J. Med. Chem. 64, 2534–2575 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Dragovich, P. S. et al. Antibody-mediated delivery of chimeric BRD4 degraders. Part 2: improvement of in vitro antiproliferation activity and in vivo antitumor efficacy. J. Med. Chem. 64, 2576–2607 (2021).

    Article  CAS  PubMed  Google Scholar 

  102. Maneiro, M. A. et al. Antibody–PROTAC conjugates enable HER2-dependent targeted protein degradation of BRD4. ACS Chem. Biol. 15, 1306–1312 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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 

  104. Hrkach, J. et al. Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Sci. Transl. Med. 4, 128ra139 (2012).

    Article  Google Scholar 

  105. Johnston, M. C. & Scott, C. J. Antibody conjugated nanoparticles as a novel form of antibody drug conjugate chemotherapy. Drug Discov. Today Technol. 30, 63–69 (2018).

    Article  PubMed  Google Scholar 

  106. Di, J., Xie, F. & Xu, Y. When liposomes met antibodies: drug delivery and beyond. Adv. Drug Deliv. Rev. 154-155, 151–162 (2020).

    Article  CAS  PubMed  Google Scholar 

  107. Cimas, F. J. et al. Controlled delivery of BET-PROTACs: in vitro evaluation of MZ1-loaded polymeric antibody conjugated nanoparticles in breast cancer. Pharmaceutics 12, 986 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Usach, I., Martinez, R., Festini, T. & Peris, J.-E. Subcutaneous injection of drugs: literature review of factors influencing pain sensation at the injection site. Adv. Ther. 36, 2986–2996 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Badkar, A. V., Gandhi, R. B., Davis, S. P. & LaBarre, M. J. Subcutaneous delivery of high-dose/volume biologics: current status and prospect for future advancements. Drug Des. Devel. Ther. 15, 159–170 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Wright, J. C. & Burgess, D. J. (eds) Long Acting Injections and Implants (Springer, 2012).

  111. Hillery, A. & Park, K. (eds) Drug Delivery: Fundamentals and Applications (CRC, 2016).

  112. O’Brien, M. N., Jiang, W., Wang, Y. & Loffredo, D. M. Challenges and opportunities in the development of complex generic long-acting injectable drug products. J. Control. Rel. 336, 144–158 (2021).

    Article  Google Scholar 

  113. Shah, J. C. & Hong, J. Model for long acting injectables (depot formulation) based on pharmacokinetics and physical chemical properties. AAPS J. 24, 44 (2022).

    Article  CAS  PubMed  Google Scholar 

  114. DeYoung, M. B., MacConnell, L., Sarin, V., Trautmann, M. & Herbert, P. Encapsulation of exenatide in poly-(d,l-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol. Ther. 13, 1145–1154 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Park, K. et al. Injectable, long-acting PLGA formulations: analyzing PLGA and understanding microparticle formation. J. Control. Rel. 304, 125–134 (2019).

    Article  CAS  Google Scholar 

  116. Robertson, J. F. R. & Harrison, M. Fulvestrant: pharmacokinetics and pharmacology. Br. J. Cancer 90, S7–S10 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Miah, A. H. et al. Optimization of a series of RIPK2 PROTACs. J. Med. Chem. 64, 12978–13003 (2021).

    Article  CAS  PubMed  Google Scholar 

  118. Vinogradov, A. A., Yin, Y. & Suga, H. Macrocyclic peptides as drug candidates: recent progress and remaining challenges. J. Am. Chem. Soc. 141, 4167–4181 (2019).

    Article  CAS  PubMed  Google Scholar 

  119. Guo, Y. et al. An integrated strategy for assessing the metabolic stability and biotransformation of macrocyclic peptides in drug discovery toward oral delivery. Anal. Chem. 94, 2032–2041 (2022).

    Article  CAS  PubMed  Google Scholar 

  120. Qian, Z., Dougherty, P. G. & Pei, D. Targeting intracellular protein–protein interactions with cell-permeable cyclic peptides. Curr. Opin. Chem. Biol. 38, 80–86 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Milletti, F. Cell-penetrating peptides: classes, origin, and current landscape. Drug Discov. Today 17, 850–860 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Xie, J. et al. Cell-penetrating peptides in diagnosis and treatment of human diseases: from preclinical research to clinical application. Front. Pharmacol. 11, 00697 (2020).

    Article  CAS  Google Scholar 

  123. Kulkarni, J. A. et al. The current landscape of nucleic acid therapeutics. Nat. Nanotechnol. 16, 630–643 (2021).

    Article  CAS  PubMed  Google Scholar 

  124. Cullis, P. R. & Hope, M. J. Lipid nanoparticle systems for enabling gene therapies. Mol. Ther. 25, 1467–1475 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Francia, V., Schiffelers, R. M., Cullis, P. R. & Witzigmann, D. The biomolecular corona of lipid nanoparticles for gene therapy. Bioconjug. Chem. 31, 2046–2059 (2020).

    Article  CAS  PubMed  Google Scholar 

  127. Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Liu, S. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 20, 701–710 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Luo, W.-C. et al. Impact of formulation on the quality and stability of freeze-dried nanoparticles. Eur. J. Pharm. Biopharm. 169, 256–267 (2021).

    Article  CAS  PubMed  Google Scholar 

  130. Dugal-Tessier, J., Thirumalairajan, S. & Jain, N. Antibody–oligonucleotide conjugates: a twist to antibody–drug conjugates. J. Clin. Med. 10, 838 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3–25 (1997).

    Article  CAS  Google Scholar 

  132. Tuntland, T. et al. Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at novartis institute of biomedical research. Front. Pharmacol. 5, 174–174 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Benet, L. Z. & Zia-Amirhosseini, P. Basic principles of pharmacokinetics. Toxicol. Pathol. 23, 115–123 (1995).

    Article  CAS  PubMed  Google Scholar 

  134. Kondic, A. et al. Navigating between right, wrong, and relevant: the use of mathematical modeling in preclinical decision making. Front. Pharmacol. 13, 860881 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Derendorf, H. & Meibohm, B. Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: concepts and perspectives. Pharm. Res. 16, 176–185 (1999).

    Article  CAS  PubMed  Google Scholar 

  136. Azer, K. et al. History and future perspectives on the discipline of quantitative systems pharmacology modeling and its applications. Front. Physiol. 12, 637999 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge their many colleagues who helped shape their thoughts on drug design and drug delivery strategies for protein degraders, including R. Green, R. Jaini, M. Landis, D. Loffredo and M. Ticehurst. In addition, the authors thank M. Landis, P. Dragovich, K. Nagapudi, J. Montgomery and M. Calabrese for their help with reviewing the manuscript.

Author information

Authors and Affiliations

  1. Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA, USA

    Matthew N. O’Brien Laramy

  2. Discovery Pharmaceutical Sciences, Merck & Co., Inc., Boston, MA, USA

    Suman Luthra

  3. Discovery Sciences, Worldwide Research, Development, and Medical, Pfizer Inc., Groton, CT, USA

    Matthew F. Brown

  4. Pharmacokinetics, Dynamics, & Metabolism, Worldwide Research, Development, and Medical, Pfizer Inc., San Diego, CA, USA

    Derek W. Bartlett

Authors
  1. Matthew N. O’Brien Laramy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Suman Luthra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew F. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Derek W. Bartlett
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.N.O.L., S.L., M.F.B. and D.W.B. all wrote and edited the perspective. D.W.B. performed PK–PD simulations.

Corresponding author

Correspondence to Matthew N. O’Brien Laramy.

Ethics declarations

Competing interests

M.N.O.L. is an employee of Genentech, Inc. S.L. is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. M.F.B. and D.W.B. are employees of Pfizer, Inc.

Peer review

Peer review information

Nature Reviews Drug Discovery thanks Alessio Ciulli, John Harling and the other, 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.

Supplementary information

Glossary

Clearance

(CL). The rate at which a drug is eliminated from the body (for example, metabolized, excreted). It represents the volume of plasma (or blood) that can be cleared of drug per unit of time and has units of volume per time.

DC50

The concentration of degrader that results in half of its maximum achievable protein of interest degradation (Dmax/2).

Dmax

The maximum amount of degradation that can be achieved for a protein of interest (POI) with a given degrader, expressed as a percentage relative to the steady-state unperturbed concentration of the POI.

Drug design space

The range of possible chemical structures that are considered by medicinal chemists during drug discovery, as constrained by physicochemical properties and synthetic capabilities.

Excipients

The components within a drug product formulation other than the active pharmaceutical ingredient.

Half-life

(t1/2). The time it takes for a given property to be reduced by half. For example, the drug t1/2 or protein of interest (POI) t1/2 represents the time for the drug concentration or the POI concentration, respectively, to reach half of the original value.

Lipophilicity

The affinity of a compound for a hydrophobic, or lipid-like, environment. Traditionally, lipophilicity is measured by an octanol/water partition coefficient, or logP. In this experiment, a compound is added to an immiscible mixture of a hydrophobic solvent (for example, octanol) and a hydrophilic solvent (for example, water), and the relative amount that is solubilized in each phase is quantified. Additional tools now exist to evaluate lipophilicity and the results are dependent on the method used.

Parenteral

Any route of administration outside the enteral or gastrointestinal tract (that is, not oral, gastric, duodenal or rectal administration). Typically used in reference to injectable routes of administration such as intravenous, intramuscular and subcutaneous.

Peak to trough

The maximum fold change in drug concentration observed during the dosing interval. It is defined as the ratio of the maximum (peak) concentration to the minimum (trough) concentration.

Protein of interest

(POI). The endogenous protein intended for targeted protein degradation.

Target binding moiety

(TBM). The portion of a bivalent protein degrader that binds to the protein of interest.

Ternary complex

The three-component complex required to drive protein degradation, comprising a bivalent protein degrader bound to a protein of interest at one terminus and an E3 ubiquitin ligase at the other end.

Therapeutic index

The ratio of the drug dose that results in toxicity to the drug dose that is required for efficacy.

Volume of distribution

(Vd). The apparent volume into which an administered drug must distribute to achieve a given concentration in plasma (or blood).

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

O’Brien Laramy, M.N., Luthra, S., Brown, M.F. et al. Delivering on the promise of protein degraders. Nat Rev Drug Discov 22, 410–427 (2023). https://doi.org/10.1038/s41573-023-00652-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41573-023-00652-2

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