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.

Targeted protein degradation: expanding the toolbox

Abstract

Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin–proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating ‘undruggable’ targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1: Substrate recruitment in targeted protein degradation.
Fig. 2: Structures of ternary complexes formed during targeted protein degradation.
Fig. 3: Tissue expression of E3 ligases.
Fig. 4: Ligandability of E3 ligases: DCAF and BTB E3 ligases.
Fig. 5: Ligandability of E3 ligases: BC-box, F-box, IAP and APC E3 ligases.
Fig. 6: Ligandability of E3 ligases: HECT and TRIM E3 ligases.

References

  1. Ravid, T. & Hochstrasser, M. Diversity of degradation signals in the ubiquitin–proteasome system. Nat. Rev. Mol. Cell Biol. 9, 679–689 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Schneekloth, A. R., Pucheault, M., Tae, H. S. & Crews, C. M. Targeted intracellular protein degradation induced by a small molecule: en route to chemical proteomics. Bioorg. Med. Chem. Lett. 18, 5904–5908 (2008).

    CAS  PubMed  Google Scholar 

  4. Itoh, Y., Ishikawa, M., Naito, M. & Hashimoto, Y. 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. 132, 5820–5826 (2010).

    CAS  PubMed  Google Scholar 

  5. Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010).

    CAS  PubMed  Google Scholar 

  6. Gandhi, A. K. et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN. Br. J. Haematol. 164, 811–821 (2014).

    CAS  PubMed  Google Scholar 

  7. Krönke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014).

    PubMed  Google Scholar 

  8. Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of ikaros proteins. Science 343, 305–309 (2014).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  10. Lai, A. C. et al. Modular PROTAC design for the degradation of oncogenic BCR–ABL. Angew. Chem. Int. Ed. 55, 807–810 (2016).

    CAS  Google Scholar 

  11. Fisher, S. L. & Phillips, A. J. Targeted protein degradation and the enzymology of degraders. Curr. Opin. Chem. Biol. 44, 47–55 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Huang, H.-T. et al. A chemoproteomic approach to query the degradable kinome using a multi-kinase degrader. Cell Chem. Biol. 25, 88–99.e6 (2018).

    CAS  PubMed  Google Scholar 

  14. Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Krönke, J. et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature 523, 183–188 (2015).

    PubMed Central  PubMed  Google Scholar 

  16. Matyskiela, M. E. et al. A cereblon modulator (CC-220) with improved degradation of ikaros and aiolos. J. Med. Chem. 61, 535–542 (2018).

    CAS  PubMed  Google Scholar 

  17. Gaudy, A. et al. SAT0225 cereblon modulator CC-220 decreases naïve and memory B cells and plasmacytoid dendritic cells in systemic lupus erythematosus (SLE) patients: exposure-response results from a phase 2A proof of concept study. Ann. Rheum. Dis. 76, 858–859 (2017).

    Google Scholar 

  18. Sun, X. et al. A chemical approach for global protein knockdown from mice to non-human primates. Cell Discov. 5, 10 (2019).

    PubMed  PubMed Central  Google Scholar 

  19. Li, Y. et al. Discovery of MD-224 as a first-in-class, highly potent, and efficacious proteolysis targeting chimera murine double minute 2 degrader capable of achieving complete and durable tumor regression. J. Med. Chem. 62, 448–466 (2019).

    CAS  PubMed  Google Scholar 

  20. Buhimschi, A. D. et al. Targeting the C481S ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation. Biochem. 57, 3564–3575 (2018).

    CAS  Google Scholar 

  21. Mullard, A. First targeted protein degrader hits the clinic. Nat. Rev. Drug Discov. 18, 237–239 (2019).

    Article  CAS  Google Scholar 

  22. Bondeson, D. P. & Crews, C. M. Targeted protein degradation by small molecules. Annu. Rev. Pharmacol. Toxicol. 57, 107–123 (2017).

    CAS  PubMed  Google Scholar 

  23. Olson, C. M. et al. Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. Nat. Chem. Biol. 14, 163–170 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  25. 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).

    CAS  PubMed  Google Scholar 

  26. Bassi, Z. I. et al. Modulating PCAF/GCN5 immune cell function through a PROTAC approach. ACS Chem. Biol. 13, 2862–2867 (2018).

    CAS  PubMed  Google Scholar 

  27. Gechijian, L. N. et al. Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands. Nat. Chem. Biol. 14, 405–412 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cromm, P. M., Samarasinghe, K. T. G., Hines, J. & Crews, C. M. Addressing kinase-independent functions of Fak via PROTAC-mediated degradation. J. Am. Chem. Soc. 140, 17019–17026 (2018).

    CAS  PubMed  Google Scholar 

  29. Smith, B. E. et al. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase. Nat. Commun. 10, 131 (2019).

    PubMed  PubMed Central  Google Scholar 

  30. Brand, M. et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem. Biol. 26, 300–306.e9 (2019).

    CAS  PubMed  Google Scholar 

  31. Zhang, X., Crowley, V. M., Wucherpfennig, T. G., Dix, M. M. & Cravatt, B. F. Electrophilic PROTACs that degrade nuclear proteins by engaging DCAF16. Nat. Chem. Biol. 15, 737–746 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Silva, M. C. et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. eLife 8, e45457 (2019).

    PubMed Central  PubMed  Google Scholar 

  33. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Buckley, D. L. et al. HaloPROTACS: use of small molecule PROTACs to induce degradation of halotag fusion proteins. ACS Chem. Biol. 10, 1831–1837 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang, L., Riley-Gillis, B., Vijay, P. & Shen, Y. Acquired resistance to BET-PROTACs (proteolysis targeting chimeras) caused by genomic alterations in core components of E3 ligase complexes. Mol. Cancer Ther. 18, 1302–1311 (2019).

    PubMed  Google Scholar 

  36. 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).

    CAS  PubMed  Google Scholar 

  37. Crew, A. P. et al. Identification and characterization of Von Hippel–Lindau-recruiting proteolysis targeting chimeras (PROTACs) of TANK-binding kinase 1. J. Med. Chem. 61, 583–598 (2018).

    CAS  PubMed  Google Scholar 

  38. Zoppi, V. et al. Iterative design and optimization of initially inactive proteolysis targeting chimeras (PROTACs) identify VZ185 as a potent, fast, and selective von Hippel–Lindau (VHL) based dual degrader probe of BRD9 and BRD7. J. Med. Chem. 62, 699–726 (2019).

    CAS  PubMed  Google Scholar 

  39. Popow, J. et al. Highly selective PTK2 proteolysis targeting chimeras to probe focal adhesion kinase scaffolding functions. J. Med. Chem. 62, 2508–2520 (2019).

    CAS  PubMed  Google Scholar 

  40. Dobrovolsky, D. et al. Bruton tyrosine kinase degradation as a therapeutic strategy for cancer. Blood 133, 952–961 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Jiang, B. et al. Development of dual and selective degraders of cyclin-dependent kinases 4 and 6. Angew. Chem. Int. Ed. 58, 6321–6326 (2019).

    CAS  Google Scholar 

  42. Powell, C. E. et al. Chemically induced degradation of anaplastic lymphoma kinase (ALK). J. Med. Chem. 61, 4249–4255 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. McCoull, W. et al. Development of a novel B-cell lymphoma 6 (BCL6) PROTAC To provide insight into small molecule targeting of BCL6. ACS Chem. Biol. 13, 3131–3141 (2018).

    CAS  PubMed  Google Scholar 

  44. Ward, C. C. et al. Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications. ACS Chem. Biol. https://doi.org/10.1021/acschembio.8b01083 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Tinworth, C. P. et al. PROTAC-mediated degradation of Bruton’s tyrosine kinase is inhibited by covalent binding. ACS Chem. Biol. 14, 342–347 (2019).

    CAS  PubMed  Google Scholar 

  46. Nowak, R. P. et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14, 706–714 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Petzold, G., Fischer, E. S. & Thomä, N. H. Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase. Nature 532, 127–130 (2016).

    CAS  PubMed  Google Scholar 

  48. Matyskiela, M. E. et al. A novel cereblon modulator recruits GSPT1 to the CRL4CRBN ubiquitin ligase. Nature 535, 252–257 (2016).

    CAS  PubMed  Google Scholar 

  49. Cardote, T. A. F., Gadd, M. S. & Ciulli, A. Crystal structure of the Cul2–Rbx1–EloBC–VHL ubiquitin ligase complex. Structure 25, 901–911.e3 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Angers, S. et al. Molecular architecture and assembly of the DDB1–CUL4A ubiquitin ligase machinery. Nature 443, 590 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Fischer, E. S. et al. The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation. Cell 147, 1024–1039 (2011).

    CAS  PubMed  Google Scholar 

  53. Drummond, M. L. & Williams, C. I. In silico modeling of PROTAC-mediated ternary complexes: validation and application. J. Chem. Inf. Model. 59, 1634–1644 (2019).

    CAS  PubMed  Google Scholar 

  54. Zorba, A. et al. Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc. Natl Acad. Sci. USA 115, E7285–E7292 (2018).

    PubMed  PubMed Central  Google Scholar 

  55. Liu, L. et al. UbiHub: a data hub for the explorers of ubiquitination pathways. Bioinformatics 35, 2882–2884 (2019).

    PubMed  PubMed Central  Google Scholar 

  56. Komander, D. & Rape, M. The ubiquitin code. Annu. Rev. Biochem. 81, 203–229 (2012).

    CAS  PubMed  Google Scholar 

  57. Chen, Z. J. & Sun, L. J. Nonproteolytic functions of ubiquitin in cell signaling. Mol. Cell 33, 275–286 (2009).

    CAS  PubMed  Google Scholar 

  58. Mészáros, B., Kumar, M., Gibson, T. J., Uyar, B. & Dosztányi, Z. Degrons in cancer. Sci. Signal. 10, eaak9982 (2017).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  60. Hines, J., Lartigue, S., Dong, H., Qian, Y. & Crews, C. M. MDM2-recruiting PROTAC offers superior, synergistic antiproliferative activity via simultaneous degradation of BRD4 and stabilization of p53. Cancer Res. 79, 251–262 (2019).

    CAS  PubMed  Google Scholar 

  61. Meyers, R. M. et al. Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells. Nat. Genet. 49, 1779–1784 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Sackton, K. L. et al. Synergistic blockade of mitotic exit by two chemical inhibitors of the APC/C. Nature 514, 646–649 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Ottis, P. et al. Assessing different E3 ligases for small molecule induced protein ubiquitination and degradation. ACS Chem. Biol. 12, 2570–2578 (2017).

    CAS  PubMed  Google Scholar 

  64. Lee, J. & Zhou, P. DCAFs, the missing link of the CUL4–DDB1 ubiquitin ligase. Mol. Cell 26, 775–780 (2007).

    CAS  PubMed  Google Scholar 

  65. Uehara, T. et al. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat. Chem. Biol. 13, 675–680 (2017).

    CAS  PubMed  Google Scholar 

  66. Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, eaal3755 (2017).

    PubMed  Google Scholar 

  67. Schapira, M., Tyers, M., Torrent, M. & Arrowsmith, C. H. WD40 repeat domain proteins: a novel target class? Nat. Rev. Drug Discov. 16, 773–786 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Cao, Q. et al. The central role of EED in the orchestration of polycomb group complexes. Nat. Commun. 5, 3127 (2014).

    PubMed  Google Scholar 

  69. He, Y. et al. The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat. Chem. Biol. 13, 389–395 (2017).

    CAS  PubMed  Google Scholar 

  70. Qi, W. et al. An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED. Nat. Chem. Biol. 13, 381–388 (2017).

    CAS  PubMed  Google Scholar 

  71. Grebien, F. et al. Pharmacological targeting of the Wdr5–MLL interaction in C/EBPα N-terminal leukemia. Nat. Chem. Biol. 11, 571–578 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Song, R., Wang, Z.-D. & Schapira, M. Disease association and druggability of WD40 repeat proteins. J. Proteome Res. 16, 3766–3773 (2017).

    CAS  PubMed  Google Scholar 

  73. Zhang, S. et al. Molecular mechanism of APC/C activation by mitotic phosphorylation. Nature 533, 260–264 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Canning, P. et al. Structural basis for Cul3 protein assembly with the BTB–Kelch family of E3 ubiquitin ligases. J. Biol. Chem. 288, 7803–7814 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhuang, M. et al. Structures of SPOP-substrate complexes: insights into molecular architectures of BTB–Cul3 ubiquitin ligases. Mol. Cell 36, 39–50 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. McMahon, M., Thomas, N., Itoh, K., Yamamoto, M. & Hayes, J. D. Dimerization of substrate adaptors can facilitate Cullin-mediated ubiquitylation of proteins by a “tethering” mechanism: a two-site interaction model for the Nrf2–Keap1 complex. J. Biol. Chem. 281, 24756–24768 (2006).

    CAS  PubMed  Google Scholar 

  77. Tong, K. I. et al. Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol. Cell. Biol. 26, 2887–2900 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang, Q. et al. Multiple Ser/Thr-rich degrons mediate the degradation of Ci/Gli by the Cul3-HIB/SPOP E3 ubiquitin ligase. Proc. Natl Acad. Sci. USA 106, 21191–21196 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 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).

    CAS  PubMed  Google Scholar 

  80. Lo, S.-C., Li, X., Henzl, M. T., Beamer, L. J. & Hannink, M. Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J. 25, 3605–3617 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Schumacher, F.-R., Sorrell, F. J., Alessi, D. R., Bullock, A. N. & Kurz, T. Structural and biochemical characterization of the KLHL3–WNK kinase interaction important in blood pressure regulation. Biochem. J. 460, 237–246 (2014).

    CAS  PubMed  Google Scholar 

  82. Chen, Z., Picaud, S., Filippakopoulos, P., D’Angiolella, V. & Bullock, A. N. Structural basis for recruitment of DAPK1 to the KLHL20 E3 ligase. Structure 27, 1–10 (2019).

    CAS  Google Scholar 

  83. Cuadrado, A. et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18, 295–317 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Davies, T. G. et al. Monoacidic inhibitors of the Kelch-like ECH-associated protein 1: nuclear factor erythroid 2-related factor 2 (KEAP1:NRF2) protein–protein interaction with high cell potency identified by fragment-based discovery. J. Med. Chem. 59, 3991–4006 (2016).

    CAS  PubMed  Google Scholar 

  85. Brockmann, M. et al. Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signalling. Nature 546, 307–311 (2017).

    CAS  PubMed  Google Scholar 

  86. Dementieva, I. S. et al. Pentameric assembly of potassium channel tetramerization domain-containing protein 5. J. Mol. Biol. 387, 175–191 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Chen, H.-Y., Liu, C.-C. & Chen, R.-H. Cul3–KLHL20 ubiquitin ligase: physiological functions, stress responses, and disease implications. Cell Div. 11, 5 (2016).

    PubMed  PubMed Central  Google Scholar 

  88. Jerabkova, K. & Sumara, I. Cullin 3, a cellular scripter of the non-proteolytic ubiquitin code. Semin. Cell Dev. Biol. 93, 100–110 (2018).

    PubMed  Google Scholar 

  89. Angers, S. et al. The KLHL12–Cullin-3 ubiquitin ligase negatively regulates the Wnt–beta-catenin pathway by targeting Dishevelled for degradation. Nat. Cell Biol. 8, 348–357 (2006).

    CAS  PubMed  Google Scholar 

  90. McGourty, C. A. et al. Regulation of the CUL3 ubiquitin ligase by a calcium-dependent Co-adaptor. Cell 167, 525–538.e14 (2016).

    CAS  PubMed  Google Scholar 

  91. Scott, D. C. et al. Two distinct types of E3 ligases work in unison to regulate substrate ubiquitylation. Cell 166, 1198–1214.e24 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Jin, L. et al. Ubiquitin-dependent regulation of COPII coat size and function. Nature 482, 495–500 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Skieterska, K., Rondou, P., Lintermans, B. & Van Craenenbroeck, K. KLHL12 promotes non-lysine ubiquitination of the dopamine receptors D4.2 and D4.4, but not of the ADHD-associated D4.7 variant. PLOS ONE 10, e0145654 (2015).

    PubMed Central  PubMed  Google Scholar 

  94. Smaldone, G. et al. Cullin 3 recognition is not a universal property among KCTD proteins. PLOS ONE 10, e0126808 (2015).

    PubMed  PubMed Central  Google Scholar 

  95. Chen, H. Y. et al. KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination. Oncogene 34, 5141–5151 (2015).

    CAS  PubMed  Google Scholar 

  96. Mahrour, N. et al. Characterization of Cullin-box sequences that direct recruitment of Cul2–Rbx1 and Cul5–Rbx2 modules to Elongin BC-based ubiquitin ligases. J. Biol. Chem. 283, 8005–8013 (2008).

    CAS  PubMed  Google Scholar 

  97. Qi, H. et al. Molecular cloning and characterization of the von Hippel–Lindau-like protein. Mol. Cancer Res. 2, 43–52 (2004).

    CAS  PubMed  Google Scholar 

  98. Koren, I. et al. The eukaryotic proteome is shaped by E3 ubiquitin ligases targeting C-terminal degrons. Cell 173, 1622–1635.e14 (2018).

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Rusnac, D.-V. et al. Recognition of the diglycine C-end degron by CRL2KLHDC2 ubiquitin ligase. Mol. Cell 72, 813–822.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Linossi, E. M. & Nicholson, S. E. The SOCS box-adapting proteins for ubiquitination and proteasomal degradation. IUBMB Life 64, 316–323 (2012).

    CAS  PubMed  Google Scholar 

  101. Guo, Y. et al. Structural basis for hijacking CBF-β and CUL5 E3 ligase complex by HIV-1 Vif. Nature 505, 229–233 (2014).

    CAS  PubMed  Google Scholar 

  102. Nucifora, F. C. et al. Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1. Nat. Commun. 7, 11792 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Kim, J. J. et al. WSB1 promotes tumor metastasis by inducing pVHL degradation. Genes Dev. 29, 2244–2257 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Zheng, S. et al. Comprehensive pan-genomic characterization of adrenocortical carcinoma. Cancer Cell 29, 723–736 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Muniz, J. R. C. et al. Molecular architecture of the ankyrin SOCS box family of Cul5-dependent E3 ubiquitin ligases. J. Mol. Biol. 425, 3166–3177 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Fei, X. et al. Crystal structure of human ASB9-2 and substrate-recognition of CKB. Protein J. 31, 275–284 (2012).

    CAS  PubMed  Google Scholar 

  107. Bergamin, E., Wu, J. & Hubbard, S. R. Structural basis for phosphotyrosine recognition by suppressor of cytokine signaling-3. Structure 14, 1285–1292 (2006).

    CAS  PubMed  Google Scholar 

  108. Kershaw, N. J. et al. SOCS3 binds specific receptor–JAK complexes to control cytokine signaling by direct kinase inhibition. Nat. Struct. Mol. Biol. 20, 469–476 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Babon, J. J. et al. The structure of SOCS3 reveals the basis of the extended SH2 domain function and identifies an unstructured insertion that regulates stability. Mol. Cell 22, 205–216 (2006).

    CAS  PubMed  Google Scholar 

  110. Filippakopoulos, P. et al. Structural basis for Par-4 recognition by the SPRY domain- and SOCS box-containing proteins SPSB1, SPSB2, and SPSB4. J. Mol. Biol. 401, 389–402 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Sadek, M. M. et al. A cyclic peptide inhibitor of the iNOS–SPSB protein–protein interaction as a potential anti-infective agent. ACS Chem. Biol. 13, 2930–2938 (2018).

    CAS  PubMed  Google Scholar 

  112. Yatsu, A., Shimada, H., Ohbayashi, N. & Fukuda, M. Rab40C is a novel Varp-binding protein that promotes proteasomal degradation of Varp in melanocytes. Biol. Open 4, 267–275 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Sakamoto, K. M. et al. Development of PROTACs to target cancer-promoting proteins for ubiquitination and degradation. Mol. Cell Proteom. 2, 1350–1358 (2003).

    CAS  Google Scholar 

  114. Qin, C. et al. Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression. J. Med. Chem. 61, 6685–6704 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Xing, W. et al. SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket. Nature 496, 64–68 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Kumanomidou, T. et al. The structural differences between a glycoprotein specific F-box protein Fbs1 and its homologous protein FBG3. PLOS ONE 10, e0140366 (2015).

    PubMed  PubMed Central  Google Scholar 

  117. Tamanini, E. et al. Discovery of a potent nonpeptidomimetic, small-molecule antagonist of cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP). J. Med. Chem. 60, 4611–4625 (2017).

    CAS  PubMed  Google Scholar 

  118. Chessari, G. et al. Fragment-based drug discovery targeting inhibitor of apoptosis proteins: discovery of a non-alanine lead series with dual activity against cIAP1 and XIAP. J. Med. Chem. 58, 6574–6588 (2015).

    CAS  PubMed  Google Scholar 

  119. Fulda, S. & Vucic, D. Targeting IAP proteins for therapeutic intervention in cancer. Nat. Rev. Drug Discov. 11, 109–124 (2012).

    CAS  PubMed  Google Scholar 

  120. 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).

    CAS  PubMed  Google Scholar 

  121. Sekine, K. et al. Small molecules destabilize cIAP1 by activating auto-ubiquitylation. J. Biol. Chem. 283, 8961–8968 (2008).

    CAS  PubMed  Google Scholar 

  122. Ohoka, N. et al. In vivo knockdown of pathogenic proteins via specific and nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent protein erasers (SNIPERs). J. Biol. Chem. 292, 4556–4570 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Peters, J.-M. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat. Rev. Mol. Cell Biol. 7, 644–656 (2006).

    CAS  PubMed  Google Scholar 

  124. Chang, L., Zhang, Z., Yang, J., McLaughlin, S. H. & Barford, D. Atomic structure of the APC/C and its mechanism of protein ubiquitination. Nature 522, 450–454 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Qi, S., O’Hayre, M., Gutkind, J. S. & Hurley, J. H. Structural and biochemical basis for ubiquitin ligase recruitment by arrestin-related domain-containing protein-3 (ARRDC3). J. Biol. Chem. 289, 4743–4752 (2014).

    CAS  PubMed  Google Scholar 

  126. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Koliopoulos, M. G. et al. Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition. Nat. Commun. 9, 1820 (2018).

    PubMed Central  PubMed  Google Scholar 

  128. Filippakopoulos, P. & Knapp, S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat. Rev. Drug Discov. 13, 337–356 (2014).

    CAS  PubMed  Google Scholar 

  129. Palmer, W. S. et al. Structure-guided design of IACS-9571, a selective high-affinity dual TRIM24–BRPF1 bromodomain inhibitor. J. Med. Chem. 59, 1440–1454 (2016).

    CAS  PubMed  Google Scholar 

  130. Allton, K. et al. Trim24 targets endogenous p53 for degradation. Proc. Natl Acad. Sci. USA 106, 11612–11616 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Dong, C. et al. Molecular basis of GID4-mediated recognition of degrons for the Pro/N-end rule pathway. Nat. Chem. Biol. 14, 466–473 (2018).

    CAS  PubMed  Google Scholar 

  132. Chen, S.-J., Wu, X., Wadas, B., Oh, J.-H. & Varshavsky, A. An N-end rule pathway that recognizes proline and destroys gluconeogenic enzymes. Science 355, eaal3655 (2017).

    PubMed  PubMed Central  Google Scholar 

  133. Neri, D. & Lerner, R. A. DNA-encoded chemical libraries: a selection system based on endowing organic compounds with amplifiable information. Annu. Rev. Biochem. 87, 479–502 (2018).

    CAS  PubMed Central  PubMed  Google Scholar 

  134. You, T. et al. Crystal structure of SPSB2 in complex with a rational designed RGD-containing cyclic peptide inhibitor of SPSB2-iNOS interaction. Biochem. Biophys. Res. Commun. 489, 346–352 (2017).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute (OGI-055, Innovative Medicines Initiative (EU/EFPIA, ULTRA-DD grant no. 115766), Janssen, Merck KGaA, Darmstadt, Germany, MSD, Novartis Pharma AG, Innovation and Science (MRIS), Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome (grant 106169/ZZ14/Z). M.S. gratefully acknowledges support from NSERC (grant RGPIN-2019-04416). Research in the C.M.C. lab is supported by grant NIH R35CA197589 and by Arvinas.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Matthieu Schapira.

Ethics declarations

Competing interests

M.F.C. is an employee of Pfizer. C.M.C. is a consultant and shareholder in Arvinas, which provides research support to his lab.

Additional information

Publisher’s note

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

Related links

Arvinas press release: http://ir.arvinas.com/news-releases/news-release-details/arvinas-present-preclinical-tau-directed-protacr-protein

The Human Protein Atlas: https://www.proteinatlas.org/

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schapira, M., Calabrese, M.F., Bullock, A.N. et al. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov 18, 949–963 (2019). https://doi.org/10.1038/s41573-019-0047-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41573-019-0047-y

This article is cited by

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