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Advancing targeted protein degradation for cancer therapy

Nature Reviews Cancer volume 21, pages 638–654 (2021)Cite this article

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Abstract

The human proteome contains approximately 20,000 proteins, and it is estimated that more than 600 of them are functionally important for various types of cancers, including nearly 400 non-enzyme proteins that are challenging to target by traditional occupancy-driven pharmacology. Recent advances in the development of small-molecule degraders, including molecular glues and heterobifunctional degraders such as proteolysis-targeting chimeras (PROTACs), have made it possible to target many proteins that were previously considered undruggable. In particular, PROTACs form a ternary complex with a hijacked E3 ubiquitin ligase and a target protein, leading to polyubiquitination and degradation of the target protein. The broad applicability of this approach is facilitated by the flexibility of individual E3 ligases to recognize different substrates. The vast majority of the approximately 600 human E3 ligases have not been explored, thus presenting enormous opportunities to develop degraders that target oncoproteins with tissue, tumour and subcellular selectivity. In this Review, we first discuss the molecular basis of targeted protein degradation. We then offer a comprehensive account of the most promising degraders in development as cancer therapies to date. Lastly, we provide an overview of opportunities and challenges in this exciting field.

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Fig. 1: Key discoveries and developments in the targeted protein degradation field.
Fig. 2: The ubiquitin–proteasome system and classification of E3 ubiquitin ligases.
Fig. 3: PROTAC degraders.

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References

  1. Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576 e16 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hart, T. et al. High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities. Cell 163, 1515–1526 (2015).

    Article  CAS  PubMed  Google Scholar 

  3. McDonald III, E. R. et al. Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell 170, 577–592 e10 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Behan, F. M. et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568, 511–516 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101–114 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. 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). This is the first publication of the PROTAC concept.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010). This is the first report that the E3 ligase CRBN is a molecular target of thalidomide.

    Article  CAS  PubMed  Google Scholar 

  8. Kronke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014). This is one of the first articles reporting the mechanism underlying the antitumour activity of IMiDs: binding of lenalidomide to CRBN induces degradation of IKZF1 and IKZF3.

    Article  PubMed  CAS  Google Scholar 

  9. Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of ikaros proteins. Science 343, 305–309 (2014). This is one of the first articles reporting the mechanism underlying the antitumour activity of IMiDs: binding of lenalidomide to CRBN induces degradation of IKZF1 and IKZF3.

    Article  CAS  PubMed  Google Scholar 

  10. 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 CRL4 CRBN. Br. J. Haematol. 164, 811–821 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Winter, G. E. et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015). This article reports the discovery of the first CRBN-recruiting PROTACs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015). This article reports the discovery of the first VHL-recruiting small-molecule PROTACs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04072952 (2019). This trial relates to the first PROTAC targeting ER to enter clinical trials for breast cancer.

  14. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03888612 (2019).

  15. 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 

  16. Sun, X. et al. PROTACs: great opportunities for academia and industry. Signal. Transduct. Target. Ther. 4, 64 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Chamberlain, P. P. & Hamann, L. G. Development of targeted protein degradation therapeutics. Nat. Chem. Biol. 15, 937–944 (2019).

    Article  CAS  PubMed  Google Scholar 

  18. Nalepa, G., Rolfe, M. & Harper, J. W. Drug discovery in the ubiquitin–proteasome system. Nat. Rev. Drug Discov. 5, 596–613 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Hershko, A. & Ciechanover, A. The ubiquitin system. Annu. Rev. Biochem. 67, 425–479 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Pickart, C. M. Mechanisms underlying ubiquitination. Annu. Rev. Biochem. 70, 503–533 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Bard, J. A. M. et al. Structure and function of the 26S proteasome. Annu. Rev. Biochem. 87, 697–724 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, W. et al. Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling. PLoS ONE 3, e1487 (2008).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Popovic, D., Vucic, D. & Dikic, I. Ubiquitination in disease pathogenesis and treatment. Nat. Med. 20, 1242–1253 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Holstein, S. A. & McCarthy, P. L. Immunomodulatory drugs in multiple myeloma: mechanisms of action and clinical experience. Drugs 77, 505–520 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. Qi, Y. & Xia, P. Cellular inhibitor of apoptosis protein-1 (cIAP1) plays a critical role in beta-cell survival under endoplasmic reticulum stress: promoting ubiquitination and degradation of C/EBP homologous protein (CHOP). J. Biol. Chem. 287, 32236–32245 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Frescas, D. & Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat. Rev. Cancer 8, 438–449 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang, Z. et al. The diverse roles of SPOP in prostate cancer and kidney cancer. Nat. Rev. Urol. 17, 339–350 (2020).

    Article  CAS  PubMed  Google Scholar 

  31. Panagopoulos, A., Taraviras, S., Nishitani, H. & Lygerou, Z. CRL4Cdt2: coupling genome stability to ubiquitination. Trends Cell Biol. 30, 290–302 (2020).

    Article  PubMed  Google Scholar 

  32. Okumura, F., Joo-Okumura, A., Nakatsukasa, K. & Kamura, T. The role of cullin 5-containing ubiquitin ligases. Cell Div. 11, 1 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  33. Buckley, D. L. et al. Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1alpha interaction. J. Am. Chem. Soc. 134, 4465–4468 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Buckley, D. L. et al. Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1alpha. Angew. Chem. Int. Ed. 51, 11463–11467 (2012).

    Article  CAS  Google Scholar 

  35. Mares, A. et al. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun. Biol. 3, 1–13 (2020).

    Article  CAS  Google Scholar 

  36. Donovan, K. A. et al. Mapping the degradable kinome provides a resource for expedited degrader development. Cell 183, 1714–1731.e10 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Schiemer, J. et al. Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes. Nat. Chem. Biol. 17, 152–160 (2021).

    Article  CAS  PubMed  Google Scholar 

  39. Daniels, D. L., Riching, K. M. & Urh, M. Monitoring and deciphering protein degradation pathways inside cells. Drug Discov. Today Technol. 31, 61–68 (2019).

    Article  PubMed  Google Scholar 

  40. 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 

  41. Gadd, M. S. et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13, 514–521 (2017). This article reports the first crystal structure of a POI–PROTAC–VHL ternary complex.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 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 

  43. Chung, C. et al. Structural insights into PROTAC-mediated degradation of Bcl-xL. ACS Chem. Biol. 15, 2316–2323 (2020).

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Hughes, S. J., Testa, A. & Ciulli, A. Crystal structure of macrocyclic PROTAC 1 in complex with the second bromodomain of human Brd4 and pVHL:elonginC:elonginB. PDB https://doi.org/10.2210/pdb6SIS/pdb (2019).

    Article  Google Scholar 

  46. Gadd, M. S., Zengerle, M. & Ciulli, A. The PROTAC MZ1 in complex with the second bromodomain of Brd4 and pVHL:elonginC:elonginB. PDB https://doi.org/10.2210/pdb5T35/pdb (2016).

    Article  Google Scholar 

  47. Roy, M., Bader, G., Diers, E., Trainor, N., Farnaby, W. & Ciulli, A. Crystal structure of PROTAC 2 in complex with the bromodomain of human SMARCA4 and pVHL:elonginC:elonginB. PDB https://doi.org/10.2210/pdb6HR2/pdb (2018).

    Article  Google Scholar 

  48. Roy, M., Bader, G., Diers, E., Trainor, N., Farnaby, W. & Ciulli, A. Crystal structure of PROTAC 2 in complex with the bromodomain of human SMARCA2 and pVHL:elonginC:elonginB. PDB https://doi.org/10.2210/pdb6HAX/pdb (2018).

    Article  Google Scholar 

  49. Roy, M., Bader, G., Diers, E., Trainor, N., Farnaby, W. & Ciulli, A. Crystal structure of PROTAC 1 in complex with the bromodomain of human SMARCA2 and pVHL:elonginC:elonginB. PDB https://doi.org/10.2210/pdb6HAY/pdb (2018).

    Article  Google Scholar 

  50. Chung, C. PROTAC6 mediated complex of VHL:EloB:EloC and Bcl-xL. PDB https://doi.org/10.2210/pdb6ZHC/pdb (2020).

    Article  Google Scholar 

  51. Nowak, R. P. et al. Plasticity in binding confers selectivity in ligand-induced protein degradation. Nat. Chem. Biol. 14, 706–714 (2018). This article reports the first crystal structures of POI–PROTAC–CRBN ternary complexes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Nowak, R. P., DeAngelo, S. L., Buckley, D., Bradner, J. E. & Fischer, E. S. Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET23 PROTAC. PDB https://doi.org/10.2210/pdb6BN7/pdb (2017).

    Article  Google Scholar 

  53. Nowak, R. P., DeAngelo, S. L., Buckley, D., Bradner, J. E. & Fischer, E. S. Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET55 PROTAC. PDB https://doi.org/10.2210/pdb6BN8/pdb (2017).

    Article  Google Scholar 

  54. Nowak, R. P., DeAngelo, S. L., Buckley, D., Bradner, J. E. & Fischer, E. Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET70 PROTAC. PDB https://doi.org/10.2210/pdb6BN9/pdb (2017).

    Article  Google Scholar 

  55. Nowak, R. P., DeAngelo, S. L., Buckley, D., Ishoey, M., He, Z., Zhang, T., Bradner, J. E. & Fischer, E. S. Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET57 PROTAC. PDB https://doi.org/10.2210/pdb6BNB/pdb (2017).

    Article  Google Scholar 

  56. Nowak, R. P., DeAngelo, S. L., Buckley, D., Bradner, J. E., Fischer, E. S. (2017) Crystal structure of DDB1-CRBN-BRD4(BD1) complex bound to dBET6 PROTAC. PDB https://doi.org/10.2210/pdb6BOY/pdb (2017)

  57. Calabrese, M. F., Schiemer, J. S. Ternary complex structure - BTK cIAP compound 17. PDB https://doi.org/10.2210/pdb6W7O/pdb (2020)

  58. Calabrese, M. F., Schiemer, J. S. Ternary complex structure - BTK cIAP compound 15. PDB https://doi.org/10.2210/pdb6W8I/pdb (2020)

  59. 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 

  60. 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).

    Article  CAS  Google Scholar 

  61. Bai, L. et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell 36, 498–511.e17 (2019). This article reports the development of the first STAT3 PROTAC with robust in vivo efficacy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Khan, S. et al. A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat. Med. 25, 1938–1947 (2019). This article reports the development of the first BCL-XL PROTAC that uses E3 expression to abrogate toxic side effects of the parental inhibitor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Ma, A. et al. Discovery of a first-in-class EZH2 selective degrader. Nat. Chem. Biol. 16, 214–222 (2020). This article reports the discovery of the first EZH2-selective degrader, which is a hydrophobic tag-based heterobifunctional small-molecule degrader.

    Article  CAS  PubMed  Google Scholar 

  66. Osborne, C. K., Wakeling, A. & Nicholson, R. I. Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br. J. Cancer 90, S2–S6 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Guan, J. et al. Therapeutic ligands antagonize estrogen receptor function by impairing its mobility. Cell 178, 949–963.e18 (2019).

    Article  CAS  PubMed  Google Scholar 

  68. Bradbury, R. H. et al. Small-molecule androgen receptor downregulators as an approach to treatment of advanced prostate cancer. Bioorg. Med. Chem. Lett. 21, 5442–5445 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Neklesa, T. K. & Crews, C. M. Greasy tags for protein removal. Nature 487, 308–309 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Long, M. J. C., Gollapalli, D. R. & Hedstrom, L. Inhibitor mediated protein degradation. Chem. Biol. 19, 629–637 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Shi, Y. et al. Boc3Arg-linked ligands induce degradation by localizing target proteins to the 20S proteasome. ACS Chem. Biol. 11, 3328–3337 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Allocati, N., Masulli, M., Di Ilio, C. & Federici, L. Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases. Oncogenesis 7, 8 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  73. Neklesa, T. K. et al. Small-molecule hydrophobic tagging–induced degradation of HaloTag fusion proteins. Nat. Chem. Biol. 7, 538–543 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xie, T. et al. Pharmacological targeting of the pseudokinase Her3. Nat. Chem. Biol. 10, 1006–1012 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Petzold, G., Fischer, E. S. & Thoma, N. H. Structural basis of lenalidomide-induced CK1alpha degradation by the CRL4CRBN ubiquitin ligase. Nature 532, 127–130 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  78. 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 

  79. Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, eaal3755 (2017). This is one of the first articles reporting sulfonamides acting as molecular glue degraders of RBM39 via binding the E3 ligase DCAF15.

    Article  PubMed  CAS  Google Scholar 

  80. Uehara, T. et al. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat. Chem. Biol. 13, 675–680 (2017). This is one of the first articles reporting sulfonamides acting as molecular glue degraders of RBM39 via binding the E3 ligase DCAF15.

    Article  CAS  PubMed  Google Scholar 

  81. Faust, T. B. et al. Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15. Nat. Chem. Biol. 16, 7–14 (2020). This is one of the first articles reporting the crystal structure of a DCAF15–molecular glue–RBM39 ternary complex.

    Article  CAS  PubMed  Google Scholar 

  82. Bussiere, D. E. et al. Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex. Nat. Chem. Biol. 16, 15–23 (2020). This is one of the first articles reporting the crystal structure of a DCAF15–molecular glue–RBM39 ternary complex.

    Article  CAS  PubMed  Google Scholar 

  83. Słabicki, M. et al. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K. Nature 585, 293–297 (2020). This is the first report that a CDK12 inhibitor can act as a moleculat glue degrader of cyclin K and it also reports the first crystal structure of the DDB1–molecular glue–CDK12–cyclin K complex.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  84. Mayor-Ruiz, C. et al. Rational discovery of molecular glue degraders via scalable chemical profiling. Nat. Chem. Biol. 16, 1199–1207 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lv, L. et al. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation. eLife 9, e59994 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Isobe, Y. et al. Manumycin polyketides act as molecular glues between UBR7 and P53. Nat. Chem. Biol. 16, 1189–1198 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Che, Y., Gilbert, A. M., Shanmugasundaram, V. & Noe, M. C. Inducing protein-protein interactions with molecular glues. Bioorg. Med. Chem. Lett. 28, 2585–2592 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  89. Han, X. et al. Discovery of ARD-69 as a highly potent proteolysis targeting chimera (PROTAC) degrader of androgen receptor (AR) for the treatment of prostate cancer. J. Med. Chem. 62, 941–964 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Kregel, S. et al. Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment. Neoplasia 22, 111–119 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhao, L., Han, X., Lu, J., McEachern, D. & Wang, S. A highly potent PROTAC androgen receptor (AR) degrader ARD-61 effectively inhibits AR-positive breast cancer cell growth in vitro and tumor growth in vivo. Neoplasia 22, 522–532 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Neklesa, T. K. et al. An oral androgen receptor PROTAC degrader for prostate cancer. J Clin Oncol. 36 (Suppl. 6), 381 (2018).

    Article  Google Scholar 

  93. 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. 38, 3500–3500 (2020). This abstract reports clinical results of the first PROTAC that has entered clinical development.

    Article  Google Scholar 

  94. Lawrence, S. et al. Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer [abstract 43]. in Proceedings of the 112th Annual Meeting of the American Association for Cancer Research (American Association for Cancer Research, 2021).

  95. Carroll, J. S. et al. Genome-wide analysis of estrogen receptor binding sites. Nat. Genet. 38, 1289–1297 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Hu, J. et al. Discovery of ERD-308 as a highly potent proteolysis targeting chimera (PROTAC) degrader of estrogen receptor (ER). J. Med. Chem. 62, 1420–1442 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Flanagan, J. et al. ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer [abstract]. Cancer Res. 79 (Suppl. 4), P5-04-18 (2018).

    Article  Google Scholar 

  98. Lawrence, S. et al. The discovery of ARV-471, an orally bioavailable estrogen receptor degrading PROTAC for the treatment of patients with breast cancer [abstract 44]. in Proceedings of the 112th Annual Meeting of the American Association for Cancer Research (American Association for Cancer Research, 2021).

  99. Chen, J. et al. Structure-based design of conformationally constrained, cell-permeable STAT3 inhibitors. ACS Med. Chem. Lett. 1, 85–89 (2010).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  100. Pentimalli, F. BCL2: A 30-year tale of life, death and much more to come. Cell Death Differ. 25, 7–9 (2018).

    Article  CAS  PubMed  Google Scholar 

  101. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Leverson, J. D. et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci. Transl. Med. 7, 279ra40 (2015).

    Article  PubMed  CAS  Google Scholar 

  103. Perini, G. F., Ribeiro, G. N., Pinto Neto, J. V., Campos, L. T. & Hamerschlak, N. BCL-2 as therapeutic target for hematological malignancies. J. Hematol. Oncol. 11, 65 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  104. Tse, C. et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 68, 3421–3428 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202–208 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Schoenwaelder, S. M. et al. Bcl-xL–inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets. Blood 118, 1663–1674 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Kaefer, A. et al. Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of navitoclax (ABT-263) induced thrombocytopenia. Cancer Chemother. Pharmacol. 74, 593–602 (2014).

    Article  CAS  PubMed  Google Scholar 

  108. Kim, K. H. & Roberts, C. W. M. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kaniskan, H. Ü., Martini, M. L. & Jin, J. Inhibitors of protein methyltransferases and demethylases. Chem. Rev. 118, 989–1068 (2018).

    Article  CAS  PubMed  Google Scholar 

  110. February, P. O. et al. First EZH2 inhibitor approved-for rare sarcoma. Cancer Discov. 10, 333–334 (2020).

    Article  Google Scholar 

  111. Kim, K. H. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491–1496 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Lawrence, C. L. & Baldwin, A. S. Non-canonical EZH2 transcriptionally activates RelB in triple negative breast cancer. PLoS ONE 11, e0165005 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  113. Kim, J. et al. Polycomb- and methylation-independent roles of EZH2 as a transcription activator. Cell Rep. 25, 2808–2820.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zhao, Y. et al. EZH2 cooperates with gain-of-function p53 mutants to promote cancer growth and metastasis. EMBO Rep. 38, e99599 (2019).

    Article  CAS  Google Scholar 

  115. Potjewyd, F. et al. Degradation of polycomb repressive complex 2 with an EED-targeted bivalent chemical degrader. Cell Chem. Biol. 27, 47–56.e15 (2020).

    Article  CAS  PubMed  Google Scholar 

  116. Hsu, J. H. R. et al. EED-targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex. Cell Chem. Biol. 27, 41–46.e17 (2020).

    Article  CAS  PubMed  Google Scholar 

  117. Liu, Z. et al. Design and synthesis of EZH2-based PROTACs to degrade the PRC2 complex for targeting the noncatalytic activity of EZH2. J. Med. Chem. https://doi.org/10.1021/acs.jmedchem.0c02234 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Shelledy, L. & Roman, D. Vemurafenib: first-in-class BRAF-mutated inhibitor for the treatment of unresectable or metastatic melanoma. J. Adv. Pract. Oncol. 6, 361–365 (2015).

    PubMed  PubMed Central  Google Scholar 

  120. Lovly, C. M. & Shaw, A. T. Molecular pathways: resistance to kinase inhibitors and implications for therapeutic strategies. Clin. Cancer Res. 20, 2249–2256 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Han, X. R. et al. Discovery of selective small molecule degraders of BRAF-V600E. J. Med. Chem. 63, 4069–4080 (2020). This is one of the first articles reporting mutant-selective BRAF PROTAC degraders.

    Article  CAS  PubMed  Google Scholar 

  122. Posternak, G. et al. Functional characterization of a PROTAC directed against BRAF mutant V600E. Nat. Chem. Biol. 16, 1170–1178 (2020). This is one of the first articles reporting mutant-selective BRAF PROTAC degraders.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Alabi, S. et al. Mutant-selective degradation by BRAF-targeting PROTACs. Nat. Commun. 12, 920 (2021). This is one of the first articles reporting mutant-selective BRAF PROTAC degraders.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hu, M. C. T., Qiu, W. R., Wang, X., Meyer, C. F. & Tan, T. H. Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes Dev. 10, 2251–2264 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Lasserre, R. et al. Release of serine/threonine-phosphorylated adaptors from signaling microclusters down-regulates T cell activation. J. Cell Biol. 195, 839–853 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hernandez, S. et al. The kinase activity of hematopoietic progenitor kinase 1 is essential for the regulation of T cell function. Cell Rep. 25, 80–94 (2018).

    Article  CAS  PubMed  Google Scholar 

  127. Si, J. et al. Hematopoietic progenitor kinase1 (HPK1) mediates T cell dysfunction and is a druggable target for T cell-based immunotherapies. Cancer Cell 38, 551–566.e11 (2020). This article reports the discovery of the first HPK1 PROTAC degrader.

    Article  CAS  PubMed  Google Scholar 

  128. Galdeano, C. et al. Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities. J. Med. Chem. 57, 8657–8663 (2014). This article reports the discovery of the first widely used ligand of the E3 ligase VHL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li, L. et al. In vivo target protein degradation induced by PROTACs based on E3 ligase DCAF15. Signal. Transduct. Target. Ther. 5, 129 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Backus, K. M. et al. Proteome-wide covalent ligand discovery in native biological systems. Nature 534, 570–574 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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). This article reports the discovery of the first DCAF16 covalent ligand and DCAF16-recruiting PROTAC degrader.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ward, C. C. et al. Covalent ligand screening uncovers a RNF4 E3 ligase recruiter for targeted protein degradation applications. ACS Chem. Biol. 14, 2430–2440 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Mahon, C., Krogan, N. J., Craik, C. S. & Pick, E. Cullin E3 ligases and their rewiring by viral factors. Biomolecules 4, 897–930 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  134. Howley, P. M., Munger, K., Romanczuk, H., Scheffner, M. & Huibregtse, J. M. Cellular targets of the oncoproteins encoded by the cancer associated human papillomaviruses. Princess Tak. Symp. 22, 239–248 (1991).

    CAS  Google Scholar 

  135. Li, T., Robert, E. I., van Breugel, P. C., Strubin, M. & Zheng, N. A promiscuous alpha-helical motif anchors viral hijackers and substrate receptors to the CUL4-DDB1 ubiquitin ligase machinery. Nat. Struct. Mol. Biol. 17, 105–111 (2010).

    Article  PubMed  CAS  Google Scholar 

  136. Simon, V., Bloch, N. & Landau, N. R. Intrinsic host restrictions to HIV-1 and mechanisms of viral escape. Nat. Immunol. 16, 546–553 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Matsson, P., Doak, B. C., Over, B. & Kihlberg, J. Cell permeability beyond the rule of 5. Adv. Drug Deliv. Rev. 101, 42–61 (2016).

    Article  CAS  PubMed  Google Scholar 

  138. Matsson, P. & Kihlberg, J. How big is too big for cell permeability? J. Med. Chem. 60, 1662–1664 (2017).

    Article  CAS  PubMed  Google Scholar 

  139. Foley, C. A., Potjewyd, F., Lamb, K. N., James, L. I. & Frye, S. V. Assessing the cell permeability of bivalent chemical degraders using the chloroalkane penetration assay. ACS Chem. Biol. 15, 290–295 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Sun, X. et al. A chemical approach for global protein knockdown from mice to non-human primates. Cell Discov. 5, 1–13 (2019).

    Article  CAS  Google Scholar 

  141. 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 

  142. 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 

  143. Goracci, L. et al. Understanding the metabolism of proteolysis targeting chimeras (PROTACs): the next step toward pharmaceutical applications. J. Med. Chem. 63, 11615–11638 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Guo, W.-H. et al. Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry. Nat. Commun. 11, 4268 (2020).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  145. Gabizon, R. et al. Efficient targeted degradation via reversible and irreversible covalent PROTACs. J. Am. Chem. Soc. 142, 11734–11742 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 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).

    Article  PubMed  Google Scholar 

  147. Ottis, P. et al. Cellular resistance mechanisms to targeted protein degradation converge toward impairment of the engaged ubiquitin transfer pathway. ACS Chem. Biol. 14, 2215–2223 (2019).

    CAS  PubMed  Google Scholar 

  148. Zhu, Y. X. et al. Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide. Blood 118, 4771–4779 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Mayor-Ruiz, C. et al. Plasticity of the cullin-RING ligase repertoire shapes sensitivity to ligand-induced protein degradation. Mol. Cell 75, 849–858 e8 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Vargesson, N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res. C. Embryo Today 105, 140–156 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Singhal, S. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 341, 1565–1571 (1999).

    Article  CAS  PubMed  Google Scholar 

  152. Franks, M. E., Macpherson, G. R. & Figg, W. D. Thalidomide. Lancet 363, 1802–1811 (2004).

    Article  CAS  PubMed  Google Scholar 

  153. Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844–848 (2004).

    Article  CAS  PubMed  Google Scholar 

  154. Zanjirband, M. & Rahgozar, S. Targeting p53-MDM2 interaction using small molecule inhibitors and the challenges needed to be addressed. Curr. Drug Targets 20, 1091–1111 (2019).

    Article  CAS  PubMed  Google Scholar 

  155. Khurana, A. & Shafer, D. A. MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388). OncoTargets Ther. 12, 2903–2910 (2019).

    Article  CAS  Google Scholar 

  156. Assi, R. et al. Final results of a phase 2, open-label study of indisulam, idarubicin, and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome. Cancer 124, 2758–2765 (2018).

    Article  CAS  PubMed  Google Scholar 

  157. Ota, K. & Uzuka, Y. Clinical trials of bestatin for leukemia and solid tumors. Biotherapy 4, 205–214 (1992).

    Article  CAS  PubMed  Google Scholar 

  158. Bodduluru, L. N., Kasala, E. R., Thota, N., Barua, C. C. & Sistla, R. Chemopreventive and therapeutic effects of nimbolide in cancer: the underlying mechanisms. Toxicol. Vitr. 28, 1026–1035 (2014).

    Article  CAS  Google Scholar 

  159. Gao, S., Wang, S. & Song, Y. Novel immunomodulatory drugs and neo-substrates. Biomark. Res. 8, 2 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Ishoey, M. et al. Translation termination factor GSPT1 is a phenotypically relevant off-target of heterobifunctional phthalimide degraders. ACS Chem. Biol. 13, 553–560 (2018).

    Article  CAS  PubMed  Google Scholar 

  161. Buhimschi, A. D. & Crews, C. M. Evolving rules for protein degradation? Insights from the zinc finger degrome. Biochemistry 58, 861–864 (2019).

    Article  CAS  PubMed  Google Scholar 

  162. Xue, G., Wang, K., Zhou, D., Zhong, H. & Pan, Z. Light-induced protein degradation with photocaged PROTACs. J. Am. Chem. Soc. 141, 18370–18374 (2019).

    Article  CAS  PubMed  Google Scholar 

  163. Reynders, M. et al. PHOTACs enable optical control of protein degradation. Sci. Adv. 6, eaay5064 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Pfaff, P., Samarasinghe, K. T. G., Crews, C. M. & Carreira, E. M. Reversible spatiotemporal control of induced protein degradation by bistable photoPROTACs. ACS Cent. Sci. 5, 1682–1690 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Naro, Y., Darrah, K. & Deiters, A. Optical control of small molecule-induced protein degradation. J. Am. Chem. Soc. 142, 2193–2197 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Liu, J. et al. Light-induced control of protein destruction by opto-PROTAC. Sci. Adv. 6, eaay5154 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Nabet, B. et al. The dTAG system for immediate and target-specific protein degradation. Nat. Chem. Biol. 14, 431–441 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bensimon, A. et al. Targeted degradation of SLC transporters reveals amenability of multi-pass transmembrane proteins to ligand-induced proteolysis. Cell Chem. Biol. 27, 728–739 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 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 

  170. Ding, Y., Fei, Y. & Lu, B. Emerging new concepts of degrader technologies. Trends Pharmacol. Sci. 41, 464–474 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 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). This is the first report of an MDM2-recruiting small-molecule PROTAC degrader of AR.

    Article  CAS  PubMed  Google Scholar 

  172. 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).

    Article  CAS  PubMed  Google Scholar 

  173. Zhao, Q., Lan, T., Su, S. & Rao, Y. Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule. Chem. Commun. 55, 369–372 (2019).

    Article  CAS  Google Scholar 

  174. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Raina, K. et al. PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer. Proc. Natl Acad. Sci. USA 113, 7124–7129 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Soares, P. et al. Group-based optimization of potent and cell-active inhibitors of the von Hippel-Lindau (VHL) E3 ubiquitin ligase: structure-activity relationships leading to the chemical probe (2S,4R)-1-((S)-2-(1-cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydr. J. Med. Chem. 61, 599–618 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  179. Donovan, K. A. et al. Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane radial ray syndrome. eLife 7, e38430 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  180. 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 

  181. Yamamoto, J. et al. ARID2 is a pomalidomide-dependent CRL4CRBN substrate in multiple myeloma cells. Nat. Chem. Biol. 16, 1208–1217 (2020).

    Article  CAS  PubMed  Google Scholar 

  182. Umezawa, H., Aoyagi, T., Suda, H., Hamada, M. & Takeuchi, T. Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes. J. Antibiot. 29, 97–99 (1976).

    Article  CAS  Google Scholar 

  183. 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). This article reports the discovery of the first BIRC2-recruiting small-molecule PROTAC degrader.

    Article  CAS  PubMed  Google Scholar 

  184. Okuhira, K. et al. Development of hybrid small molecules that induce degradation of estrogen receptor-alpha and necrotic cell death in breast cancer cells. Cancer Sci. 104, 1492–1498 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Ohoka, N. et al. Cancer cell death induced by novel small molecules degrading the TACC3 protein via the ubiquitin-proteasome pathway. Cell Death Dis. 5, e1513 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Okuhira, K. et al. Molecular design, synthesis, and evaluation of SNIPER(ER) That induces proteasomal degradation of ERalpha. Methods Mol. Biol. 1366, 549–560 (2016).

    Article  CAS  PubMed  Google Scholar 

  187. Shibata, N. et al. Development of protein degradation inducers of oncogenic BCR-ABL protein by conjugation of ABL kinase inhibitors and IAP ligands. Cancer Sci. 108, 1657–1666 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Shibata, N. et al. Development of protein degradation inducers of androgen receptor by conjugation of androgen receptor ligands and inhibitor of apoptosis protein ligands. J. Med. Chem. 61, 543–575 (2018).

    Article  CAS  PubMed  Google Scholar 

  189. Ohoka, N. et al. Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor alpha degradation. J. Biol. Chem. 293, 6776–6790 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Zandvliet, A. S., Schellens, J. H., Copalu, W., Beijnen, J. H. & Huitema, A. D. Covariate-based dose individualization of the cytotoxic drug indisulam to reduce the risk of severe myelosuppression. J. Pharmacokinet. Pharmacodyn. 36, 39–62 (2009).

    Article  CAS  PubMed  Google Scholar 

  191. Kirkwood, J. M. et al. A phase 2 study of tasisulam sodium (LY573636 sodium) as second-line treatment for patients with unresectable or metastatic melanoma. Cancer 117, 4732–4739 (2011).

    Article  CAS  PubMed  Google Scholar 

  192. Ting, T. C. et al. Aryl sulfonamides degrade RBM39 and RBM23 by recruitment to CRL4-DCAF15. Cell Rep. 29, 1499–1510 e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Spradlin, J. N. et al. Harnessing the anti-cancer natural product nimbolide for targeted protein degradation. Nat. Chem. Biol. 15, 747–755 (2019). This article reports the discovery of the first RNF114 covalent ligand and RNF114-recruiting PROTAC degrader.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Zhang, C. et al. Proteolysis targeting chimeras (PROTACs) of anaplastic lymphoma kinase (ALK). Eur. J. Med. Chem. 151, 304–314 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Kang, C. H. et al. Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC). Biochem. Biophys. Res. Commun. 505, 542–547 (2018).

    Article  CAS  PubMed  Google Scholar 

  196. Zhao, Q. et al. Discovery of SIAIS178 as an effective BCR-ABL degrader by recruiting von Hippel-Lindau (VHL) E3 ubiquitin ligase. J. Med. Chem. 62, 9281–9298 (2019).

    Article  CAS  PubMed  Google Scholar 

  197. Bai, L. et al. Targeted degradation of BET proteins in triple-negative breast cancer. Cancer Res. 77, 2476–2487 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Sun, Y. et al. Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas. Leukemia 33, 2105–2110 (2019).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Chi, J. J. et al. A novel strategy to block mitotic progression for targeted therapy. EBioMedicine 49, 40–54 (2019).

    Article  PubMed  Google Scholar 

  201. Wu, X. et al. Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders. Nat. Cancer 138, S5 (2021).

    Google Scholar 

  202. 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 

  203. Burslem, G. M., Song, J., Chen, X., Hines, J. & Crews, C. M. Enhancing antiproliferative activity and selectivity of a FLT-3 inhibitor by proteolysis targeting chimera conversion. J. Am. Chem. Soc. 140, 16428–16432 (2018).

    Article  CAS  PubMed  Google Scholar 

  204. 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).

    Article  CAS  PubMed  Google Scholar 

  205. Wei, J. et al. Discovery of a first-in-class mitogen-activated protein kinase kinase 1/2 degrader. J. Med. Chem. 62, 10897–10911 (2019).

    Article  CAS  PubMed  Google Scholar 

  206. Hu, J. et al. Potent and selective mitogen-activated protein kinase kinase 1/2 (MEK1/2) heterobifunctional small-molecule degraders. J. Med. Chem. 63, 15883–15905 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Shen, Y. et al. Discovery of first-in-class protein arginine methyltransferase 5 (PRMT5) degraders. J. Med. Chem. 63, 9977–9989 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Song, Y. et al. Development and preclinical validation of a novel covalent ubiquitin receptor Rpn13 degrader in multiple myeloma. Leukemia 33, 2685–2694 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Chen, L. et al. Discovery of first-in-class potent and selective tropomyosin receptor kinase degraders. J. Med. Chem. 63, 14562–14575 (2020).

    Article  CAS  PubMed  Google Scholar 

  210. Scheffner, M., Nuber, U. & Huibregtse, J. M. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature 373, 81–83 (1995).

    Article  CAS  PubMed  Google Scholar 

  211. Ozkan, E., Yu, H. & Deisenhofer, J. Mechanistic insight into the allosteric activation of a ubiquitin-conjugating enzyme by RING-type ubiquitin ligases. Proc. Natl Acad. Sci. USA 102, 18890–18895 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Plechanovova, A., Jaffray, E. G., Tatham, M. H., Naismith, J. H. & Hay, R. T. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489, 115–120 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Pruneda, J. N. et al. Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Mol. Cell 47, 933–942 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Dou, H., Buetow, L., Sibbet, G. J., Cameron, K. & Huang, D. T. BIRC7-E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nat. Struct. Mol. Biol. 19, 876–883 (2012).

    Article  CAS  PubMed  Google Scholar 

  215. Berndsen, C. E. & Wolberger, C. New insights into ubiquitin E3 ligase mechanism. Nat. Struct. Mol. Biol. 21, 301–307 (2014).

    Article  CAS  PubMed  Google Scholar 

  216. Zheng, N. et al. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 416, 703–709 (2002).

    Article  CAS  PubMed  Google Scholar 

  217. Zimmerman, E. S., Schulman, B. A. & Zheng, N. Structural assembly of cullin-RING ubiquitin ligase complexes. Curr. Opin. Struct. Biol. 20, 714–721 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Skowyra, D., Craig, K. L., Tyers, M., Elledge, S. J. & Harper, J. W. F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell 91, 209–219 (1997).

    Article  CAS  PubMed  Google Scholar 

  219. Feldman, R. M., Correll, C. C., Kaplan, K. B. & Deshaies, R. J. A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiquitination of the phosphorylated CDK inhibitor Sic1p. Cell 91, 221–230 (1997).

    Article  CAS  PubMed  Google Scholar 

  220. Pause, A. et al. The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc. Natl Acad. Sci. USA 94, 2156–2161 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Lisztwan, J., Imbert, G., Wirbelauer, C., Gstaiger, M. & Krek, W. The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Genes Dev. 13, 1822–1833 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Kamura, T. et al. Muf1, a novel elongin BC-interacting leucine-rich repeat protein that can assemble with Cul5 and Rbx1 to reconstitute a ubiquitin ligase. J. Biol. Chem. 276, 29748–29753 (2001).

    Article  CAS  PubMed  Google Scholar 

  223. Shiyanov, P., Nag, A. & Raychaudhuri, P. Cullin 4A associates with the UV-damaged DNA-binding protein DDB. J. Biol. Chem. 274, 35309–35312 (1999).

    Article  CAS  PubMed  Google Scholar 

  224. Kamura, T. et al. The elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes. Dev. 12, 3872–3881 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Kamura, T. et al. VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases. Genes Dev. 18, 3055–3065 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Jin, J., Arias, E. E., Chen, J., Harper, J. W. & Walter, J. C. A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1. Mol. Cell 23, 709–721 (2006).

    Article  CAS  PubMed  Google Scholar 

  227. Angers, S. et al. Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery. Nature 443, 590–593 (2006).

    Article  CAS  PubMed  Google Scholar 

  228. Higa, L. A. et al. CUL4-DDB1 ubiquitin ligase interacts with multiple WD40-repeat proteins and regulates histone methylation. Nat. Cell Biol. 8, 1277–1283 (2006).

    Article  CAS  PubMed  Google Scholar 

  229. He, Y. J., McCall, C. M., Hu, J., Zeng, Y. & Xiong, Y. DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4-ROC1 ubiquitin ligases. Genes Dev. 20, 2949–2954 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Pintard, L. et al. The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase. Nature 425, 311–316 (2003).

    Article  CAS  PubMed  Google Scholar 

  231. Xu, L. et al. BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature 425, 316–321 (2003).

    Article  CAS  PubMed  Google Scholar 

  232. Geyer, R., Wee, S., Anderson, S., Yates, J. & Wolf, D. A. BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases. Mol. Cell 12, 783–790 (2003).

    Article  CAS  PubMed  Google Scholar 

  233. Furukawa, M., He, Y. J., Borchers, C. & Xiong, Y. Targeting of protein ubiquitination by BTB-cullin 3-Roc1 ubiquitin ligases. Nat. Cell Biol. 5, 1001–1007 (2003).

    Article  CAS  PubMed  Google Scholar 

  234. Wang, Z., Liu, P., Inuzuka, H. & Wei, W. Roles of F-box proteins in cancer. Nat. Rev. Cancer 14, 233–247 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  236. Wang, P., Song, J. & Ye, D. CRL3s: the BTB-CUL3-RING E3 ubiquitin ligases in Cullin-RING Ligases and Protein Neddylation: Biology and Therapeutics (eds Sun, Y., Wei, W. & Jin, J.) 211–223 (Springer, 2020).

  237. Braschi B. et al. RING finger proteins. HGNC Database, HUGO Gene Nomenclature Committee, European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton. https://www.genenames.org/data/genegroup/#!/group/58%0A (2020).

  238. Sarikas, A., Hartmann, T. & Pan, Z.-Q. The cullin protein family. Genome Biol. 12, 220 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Goldenberg, S. J. et al. Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubiquitin ligases. Cell 119, 517–528 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Fischer, E. S. et al. Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014). This article reports one of the first crystal structures of DDB1–CRBN–IMiD complexes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  243. Liu, J. & Nussinov, R. Rbx1 flexible linker facilitates cullin-RING ligase function before neddylation and after deneddylation. Biophys. J. 99, 736–744 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Scott, D. C. et al. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 157, 1671–1684 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Baek, K. et al. NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly. Nature 578, 461–466 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Grossman, R. L. et al. Toward a shared vision for cancer genomic data. N. Engl. J. Med. 375, 1109–1112 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  247. Oliner, J. D., Saiki, A. Y. & Caenepeel, S. The role of MDM2 amplification and overexpression in tumorigenesis. Cold Spring Harb. Perspect. Med. 6, a026336 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  248. Pi, L. et al. Evaluating dose-limiting toxicities of MDM2 inhibitors in patients with solid organ and hematologic malignancies: a systematic review of the literature. Leuk. Res. 86, 106222 (2019).

    Article  CAS  PubMed  Google Scholar 

  249. Liu, Y. & Mallampalli, R. K. Small molecule therapeutics targeting F-box proteins in cancer. Semin. Cancer Biol. 36, 105–119 (2016).

    Article  PubMed  CAS  Google Scholar 

  250. Simonetta, K. R. et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun. 10, 1402 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Guo, Z. Q. et al. Small-molecule targeting of E3 ligase adaptor SPOP in kidney cancer. Cancer Cell 30, 474–484 (2016).

    Article  CAS  PubMed  Google Scholar 

  253. Wang, D. et al. A deep proteome and transcriptome abundance atlas of 29 healthy human tissues. Mol. Syst. Biol. 15, 1–16 (2019).

    Article  CAS  Google Scholar 

  254. Chamberlain, P. P. et al. Structure of the human cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs. Nat. Struct. Mol. Biol. 21, 803–809 (2014). This article reports one of the first crystal structures of DDB1–CRBN–IMiD complexes.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank J. Na for helping with DDB1 and CUL5 structural analysis and K. Lu for helping search for references. J.J. acknowledges support from the US National Institutes of Health (grants R01CA218600, R01CA230854, R01CA260666, R01GM122749, R01HD088626 and P30CA196521 from) and an endowed professorship from the Icahn School of Medicine at Mount Sinai. Y.X. acknowledges support from the US National Institutes of Health (grant R01GM067113) and an endowed professorship from the University of North Carolina at Chapel Hill. B.D. acknowledges support from the Medical Scientist Training Program (training grant T32GM007280) at the Icahn School of Medicine at Mount Sinai and the US National Institutes of Health (grant 3R01CA230854-03S1).

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Author notes

  1. These authors contributed equally: Brandon Dale, Meng Cheng.

Authors and Affiliations

  1. Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Brandon Dale, Kwang-Su Park, H. Ümit Kaniskan & Jian Jin

  2. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Brandon Dale, Kwang-Su Park, H. Ümit Kaniskan & Jian Jin

  3. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Brandon Dale, Kwang-Su Park, H. Ümit Kaniskan & Jian Jin

  4. Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Brandon Dale, Kwang-Su Park, H. Ümit Kaniskan & Jian Jin

  5. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Meng Cheng & Yue Xiong

  6. Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Meng Cheng & Yue Xiong

  7. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Yue Xiong

  8. Cullgen Inc., San Diego, CA, USA

    Yue Xiong

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Contributions

B.D. and M.C. contributed equally to this work. All authors researched data for the manuscript and contributed to discussion of the content and writing and editing of the manuscript.

Corresponding authors

Correspondence to Yue Xiong or Jian Jin.

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Competing interests

J.J., Y.X., H.Ü.K. and M.C. are inventors named on patent applications filed by the Icahn School of Medicine at Mount Sinai and the University of North Carolina at Chapel Hill. The Jin laboratory has received research funds from Celgene Corporation, Levo Therapeutics and Cullgen, Inc. The Xiong laboratory has received research funds from Cullgen Inc. J.J. is an equity shareholder in and consultant for Cullgen Inc. Y.X. is an equity shareholder in and currently an employee of Cullgen, Inc. B.D. and K-S.P. declare no competing interests.

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Nature Reviews Cancer thanks R. Deshaies, F. Ferguson, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related Links

DRIVE Data Portal: https://oncologynibr.shinyapps.io/drive/

Expression Atlas Database: https://www.ebi.ac.uk/gxa/experiments/E-PROT-29/Results

Hugo Gene Nomenclature Committee: https://www.genenames.org/

National Cancer Institute Genomic Data Commons: https://portal.gdc.cancer.gov/projects

RCSB Protein Data Bank: https://www.rcsb.org/

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

UniProt Knowledgebase: https://www.uniprot.org/help/uniprotkb

Supplementary information

Glossary

26S proteasome

A 2.5-MDa proteolytic protein complex that controls protein homeostasis and specific cellular process in all eukaryotes.

Immunomodulatory imide drugs

(IMiDs). A class of small molecules that have been used in the clinic to modulate the immune system via binding the E3 ligase cereblon (CRBN). IMiDs recruit neosubstrates to CRBN for ubiquitination and subsequent degradation and have often been used as E3 ligands in proteolysis-targeting chimeras (PROTACs).

Molecular glues

Small molecules that act like adhesives to induce or stabilize protein–protein interactions between an E3 ligase and a neosubstrate, leading to degradation of the neosubstrate.

Neosubstrates

Substrates of an E3 ligase that are not recognized by the E3 ligase under physiological conditions but interact with the E3 ligase in the presence of a molecular glue.

HECT

The HECT domain, which is approximately 350 amino acids long and homologous to the E6AP carboxy terminus (HECT), contains an evolutionarily conserved cysteine residue that forms a thioester linkage with ubiquitin.

RBR

A tripartite domain of approximately 140 amino acid in length, consisting of three zinc-binding domains, RING1–IBR–RIGN2. RING1-in-between-RIGN2 (RBR) ligases combine mechanistic features of RING-type and homologous to the E6AP carboxy terminus (HECT)-type ligases by using RING1 to recognize the E2~ubiquitin complex (the tilde denotes a high-energy thioester bond) and RING2 to form the thioester intermediate with ubiquitin.

RING finger

First identified as a novel cysteine-rich sequence motif present in the ‘really interesting new gene’ (RING1). RING fingers promote the transfer of ubiquitin directly from E2 to the substrate by locking the E2~ubiqution conjugate (the tilde denotes a high-energy thioester bond) in a closed conformation.

SKP1

S-phase kinase associated protein 1 (SKP1) binds CUL1 and functions as the adaptor protein for CRL1 complexes.

Elongin B–elongin C complex

A heterodimer that functions as the adaptor protein complex for both CRL2 and CRL5.

F-box

A domain, first identified in cyclin F, approximately 40 amino acids long that binds the adaptor protein SKP1 and functions as the substrate receptors for CRL1 complexes.

SOCS box

An approximately 40 amino acid region originally identified in members of suppressors of cytokine signalling proteins that consists of two separate sequences, one for binding the elongin B–elongin C heterodimer (BC box) and one for binding CUL5 (CUL5 box).

WD40 repeat

A domain defined at the primary sequence level by a Gly-His dipeptide and a Trp-Asp (WD) dipeptide separated by 20–30 residues that is commonly found in many proteins of diverse function and typically forms β-propeller structures.

BTB domain

Also known as the POZ domain, a conserved domain of 115–130 residues that consists of five α-helices and binds the amino-terminal domain of CUL3 and functions as the substrate receptor for cullin 3-RING ligase (CRL3) complexes.

Cooperative binding

The enhanced binding of a proteolysis-targeting chimera (PROTAC) to both the protein of interest and the E3 ligase compared with the binding of the PROTAC to the protein of interest or the E3 ligase alone.

Unfolded protein response

A cellular stress response that is activated by high levels of misfolded or unfolded proteins in the endoplasmic reticulum. The unfolded protein response aims to decrease the amount of unfolded proteins to maintain cellular function or induce apoptosis when this cannot be achieved.

DDB1- and CUL4-associated factor

(DCAF). A member of a family of proteins also known as DDB1-binding WD40 (DWD) proteins that bind DDB1 and function as substrate receptors for CRL4 complexes.

DDB1

Damaged DNA-binding protein complex subunit 1 (DDB1) binds CUL4 and functions as an adaptor protein for cullin 4-RING ligase (CRL4) complexes.

Degron motif

A specific molecular feature that is recognized by E3 ligases.

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Dale, B., Cheng, M., Park, KS. et al. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer 21, 638–654 (2021). https://doi.org/10.1038/s41568-021-00365-x

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