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Cited by 286Protein Degradation and InhibitorsUbiquitin and proteasome pathwaysChemical Synthesis and Analysis

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PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

Open access
He, Ming, Cao, Chaoguo, Ni, Zhihao, Liu, Yongbo, Song, Peilu, Hao, Shuang, He, Yuna, Sun, Xiuyun, Rao, Yu·2022·Signal Transduction and Targeted Therapy
DOI 10.1038/s41392-022-00999-9PMC PMC9178337
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Abstract

PROteolysis TArgeting Chimeras (PROTACs) technology is a new protein-degradation strategy that has emerged in recent years. It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system. PROTACs can not only be used as potential clinical treatments for diseases such as cancer, immune disorders, viral infections, and neurodegenerative diseases, but also provide unique chemical knockdown tools for biological research in a catalytic, reversible, and rapid manner. In 2019, our group published a review article “PROTACs: great opportunities for academia and industry” in the journal, summarizing the representative compounds of PROTACs reported before the end of 2019. In the past 2 years, the entire field of protein degradation has experienced rapid development, including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage. In addition to PROTAC and molecular glue technology, other new degradation technologies are also developing rapidly. In this article, we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation. The problems that need to be solved in this field will also be briefly introduced.

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Figures

Fig. 1 The mechanism of PROTAC-mediated protein degradation
Fig. 1 The mechanism of PROTAC-mediated protein degradationCC BY · PubMed Central
Fig. 2 The researches on PROTAC from 2001 to 2021. a The publications on PROTACs from 2001 to 2021. b The structure of ARV-110 and ARV-471. c The comparison of PROTAC targets on different diseases between 2001–2019 and 2001–2021. d Classification and percentage of degradable kinases
Fig. 2 The researches on PROTAC from 2001 to 2021. a The publications on PROTACs from 2001 to 2021. b The structure of ARV-110 and ARV-471. c The comparison of PROTAC targets on different diseases between 2001–2019 and 2001–2021. d Classification and percentage of degradable kinasesCC BY · PubMed Central
Fig. 3 The list of human “degradable” kinases based on PROTAC
Fig. 3 The list of human “degradable” kinases based on PROTACCC BY · PubMed Central
Fig. 4 The representative PROTACs targeting AR
Fig. 4 The representative PROTACs targeting ARCC BY · PubMed Central
Fig. 5 The representative PROTACs targeting BRAF and BRAFV600E
Fig. 5 The representative PROTACs targeting BRAF and BRAFV600ECC BY · PubMed Central
Fig. 6 The representative PROTAC targeting eEF2K
Fig. 6 The representative PROTAC targeting eEF2KCC BY · PubMed Central
Fig. 7 The representative PROTACs targeting EGFR
Fig. 7 The representative PROTACs targeting EGFRCC BY · PubMed Central
Fig. 8 The representative PROTACs targeting eIF4E
Fig. 8 The representative PROTACs targeting eIF4ECC BY · PubMed Central
Fig. 9 The representative PROTACs targeting ER
Fig. 9 The representative PROTACs targeting ERCC BY · PubMed Central
Fig. 10 The representative PROTAC targeting FGFR1/2
Fig. 10 The representative PROTAC targeting FGFR1/2CC BY · PubMed Central
Fig. 11 The representative PROTACs targeting IGF-1R and Src
Fig. 11 The representative PROTACs targeting IGF-1R and SrcCC BY · PubMed Central
Fig. 12 The representative PROTACs targeting KRASG12C
Fig. 12 The representative PROTACs targeting KRASG12CCC BY · PubMed Central
Fig. 13 The representative PROTACs targeting MEK
Fig. 13 The representative PROTACs targeting MEKCC BY · PubMed Central
Fig. 14 The representative PROTAC targeting Myc
Fig. 14 The representative PROTAC targeting MycCC BY · PubMed Central
Fig. 15 The representative PROTACs targeting p38
Fig. 15 The representative PROTACs targeting p38CC BY · PubMed Central
Fig. 16 The representative PROTACs targeting PDEδ
Fig. 16 The representative PROTACs targeting PDEδCC BY · PubMed Central
Fig. 17 The representative PROTACs targeting SHP2
Fig. 17 The representative PROTACs targeting SHP2CC BY · PubMed Central
Fig. 18 The representative PROTACs targeting AKT
Fig. 18 The representative PROTACs targeting AKTCC BY · PubMed Central
Fig. 19 The representative PROTACs targeting ALK
Fig. 19 The representative PROTACs targeting ALKCC BY · PubMed Central
Fig. 20 The representative PROTACs targeting Bcl-xl
Fig. 20 The representative PROTACs targeting Bcl-xlCC BY · PubMed Central
Fig. 21 The representative PROTACs targeting BCR-ABL
Fig. 21 The representative PROTACs targeting BCR-ABLCC BY · PubMed Central
Fig. 22 The representative PROTACs targeting FAK
Fig. 22 The representative PROTACs targeting FAKCC BY · PubMed Central
Fig. 23 The representative PROTACs targeting MDM2
Fig. 23 The representative PROTACs targeting MDM2CC BY · PubMed Central
Fig. 24 The representative PROTACs targeting FLT3
Fig. 24 The representative PROTACs targeting FLT3CC BY · PubMed Central
Fig. 25 The representative PROTACs targeting JAK
Fig. 25 The representative PROTACs targeting JAKCC BY · PubMed Central
Fig. 26 The representative PROTAC targeting STAT3
Fig. 26 The representative PROTAC targeting STAT3CC BY · PubMed Central
Fig. 27 The representative PROTAC targeting β-catenin
Fig. 27 The representative PROTAC targeting β-cateninCC BY · PubMed Central
Fig. 28 The representative PROTAC targeting FOXM1
Fig. 28 The representative PROTAC targeting FOXM1CC BY · PubMed Central
Fig. 29 The representative PROTAC targeting α1A-AR
Fig. 29 The representative PROTAC targeting α1A-ARCC BY · PubMed Central
Fig. 30 The representative PROTACs targeting BRD
Fig. 30 The representative PROTACs targeting BRDCC BY · PubMed Central
Fig. 31 The representative PROTAC targeting CBP and p300
Fig. 31 The representative PROTAC targeting CBP and p300CC BY · PubMed Central
Fig. 32 The representative PROTAC targeting ENL
Fig. 32 The representative PROTAC targeting ENLCC BY · PubMed Central
Fig. 33 The representative PROTACs targeting HDAC
Fig. 33 The representative PROTACs targeting HDACCC BY · PubMed Central
Fig. 34 The representative PROTAC targeting KDM5C
Fig. 34 The representative PROTAC targeting KDM5CCC BY · PubMed Central
Fig. 35 The representative PROTAC targeting NAMPT
Fig. 35 The representative PROTAC targeting NAMPTCC BY · PubMed Central
Fig. 36 The representative PROTAC targeting NSD3
Fig. 36 The representative PROTAC targeting NSD3CC BY · PubMed Central
Fig. 37 The representative PROTACs targeting PRC2 (EZH2, EED)
Fig. 37 The representative PROTACs targeting PRC2 (EZH2, EED)CC BY · PubMed Central
Fig. 38 The representative PROTAC targeting PRMT5
Fig. 38 The representative PROTAC targeting PRMT5CC BY · PubMed Central
Fig. 39 The representative PROTAC targeting SIRT2
Fig. 39 The representative PROTAC targeting SIRT2CC BY · PubMed Central
Fig. 40 The representative PROTACs targeting WDR5
Fig. 40 The representative PROTACs targeting WDR5CC BY · PubMed Central
Fig. 41 The representative PROTACs targeting Aurora A
Fig. 41 The representative PROTACs targeting Aurora ACC BY · PubMed Central
Fig. 42 The representative PROTAC targeting Cdc20
Fig. 42 The representative PROTAC targeting Cdc20CC BY · PubMed Central
Fig. 43 The representative PROTACs targeting CDK2
Fig. 43 The representative PROTACs targeting CDK2CC BY · PubMed Central
Fig. 44 The representative PROTAC targeting CDK2/5
Fig. 44 The representative PROTAC targeting CDK2/5CC BY · PubMed Central
Fig. 45 The representative PROTACs targeting CDK2/4/6
Fig. 45 The representative PROTACs targeting CDK2/4/6CC BY · PubMed Central
Fig. 46 The representative PROTACs targeting CDK9
Fig. 46 The representative PROTACs targeting CDK9CC BY · PubMed Central
Fig. 47 The representative PROTACs targeting CDK12
Fig. 47 The representative PROTACs targeting CDK12CC BY · PubMed Central
Fig. 48 The representative PROTAC targeting Wee1
Fig. 48 The representative PROTAC targeting Wee1CC BY · PubMed Central
Fig. 49 The representative PROTACs targeting CRBN
Fig. 49 The representative PROTACs targeting CRBNCC BY · PubMed Central
Fig. 50 The representative PROTAC targeting hRpn13Pru
Fig. 50 The representative PROTAC targeting hRpn13PruCC BY · PubMed Central
Fig. 51 The representative PROTAC targeting VHL
Fig. 51 The representative PROTAC targeting VHLCC BY · PubMed Central
Fig. 52 The representative PROTAC targeting ZFP91
Fig. 52 The representative PROTAC targeting ZFP91CC BY · PubMed Central
Fig. 53 The representative PROTACs targeting BTK
Fig. 53 The representative PROTACs targeting BTKCC BY · PubMed Central
Fig. 54 The representative PROTAC targeting CCR9
Fig. 54 The representative PROTAC targeting CCR9CC BY · PubMed Central
Fig. 55 The representative PROTAC targeting CD147
Fig. 55 The representative PROTAC targeting CD147CC BY · PubMed Central
Fig. 56 The representative PROTAC targeting CRABP
Fig. 56 The representative PROTAC targeting CRABPCC BY · PubMed Central
Fig. 57 The representative PROTAC targeting HSP90
Fig. 57 The representative PROTAC targeting HSP90CC BY · PubMed Central
Fig. 58 The representative PROTAC targeting IDO1
Fig. 58 The representative PROTAC targeting IDO1CC BY · PubMed Central
Fig. 59 The representative PROTAC targeting LXR-β
Fig. 59 The representative PROTAC targeting LXR-βCC BY · PubMed Central
Fig. 60 The representative PROTAC targeting MIF
Fig. 60 The representative PROTAC targeting MIFCC BY · PubMed Central
Fig. 61 The representative PROTACs targeting PARP1
Fig. 61 The representative PROTACs targeting PARP1CC BY · PubMed Central
Fig. 62 The representative PROTAC targeting PARP14
Fig. 62 The representative PROTAC targeting PARP14CC BY · PubMed Central
Fig. 63 The representative PROTACs targeting PD-L1
Fig. 63 The representative PROTACs targeting PD-L1CC BY · PubMed Central
Fig. 64 The representative PROTAC targeting PLK1
Fig. 64 The representative PROTAC targeting PLK1CC BY · PubMed Central
Fig. 65 The representative PROTAC targeting RAR
Fig. 65 The representative PROTAC targeting RARCC BY · PubMed Central
Fig. 66 The representative PROTAC targeting RHAU
Fig. 66 The representative PROTAC targeting RHAUCC BY · PubMed Central
Fig. 67 The representative PROTAC targeting RIPK2
Fig. 67 The representative PROTAC targeting RIPK2CC BY · PubMed Central
Fig. 68 The representative PROTAC targeting SF3B1
Fig. 68 The representative PROTAC targeting SF3B1CC BY · PubMed Central
Fig. 69 The representative PROTAC targeting SLC
Fig. 69 The representative PROTAC targeting SLCCC BY · PubMed Central
Fig. 70 The representative PROTACs targeting SMARCA2/4
Fig. 70 The representative PROTACs targeting SMARCA2/4CC BY · PubMed Central
Fig. 71 The representative PROTAC targeting SRC-1
Fig. 71 The representative PROTAC targeting SRC-1CC BY · PubMed Central
Fig. 72 The representative PROTAC targeting tyrosinase
Fig. 72 The representative PROTAC targeting tyrosinaseCC BY · PubMed Central
Fig. 73 The representative PROTACs targeting pan-coronavirus antiviral
Fig. 73 The representative PROTACs targeting pan-coronavirus antiviralCC BY · PubMed Central
Fig. 74 The representative PROTACs targeting SARS-CoV-2
Fig. 74 The representative PROTACs targeting SARS-CoV-2CC BY · PubMed Central
Fig. 75 The representative PROTACs targeting HDAC3
Fig. 75 The representative PROTACs targeting HDAC3CC BY · PubMed Central
Fig. 76 The representative PROTACs targeting H-PGDS
Fig. 76 The representative PROTACs targeting H-PGDSCC BY · PubMed Central
Fig. 77 The representative PROTAC targeting IRAK1
Fig. 77 The representative PROTAC targeting IRAK1CC BY · PubMed Central
Fig. 78 The representative PROTAC targeting IRAK3
Fig. 78 The representative PROTAC targeting IRAK3CC BY · PubMed Central
Fig. 79 The representative PROTACs targeting IRAK4
Fig. 79 The representative PROTACs targeting IRAK4CC BY · PubMed Central
Fig. 80 The representative PROTACs targeting neurodegenerative diseases
Fig. 80 The representative PROTACs targeting neurodegenerative diseasesCC BY · PubMed Central
Fig. 81 The representative PROTACs targeting Cas protein, HMGCR and VEGFR2
Fig. 81 The representative PROTACs targeting Cas protein, HMGCR and VEGFR2CC BY · PubMed Central
Fig. 82 The representative PROTACs of antibody-PROTAC
Fig. 82 The representative PROTACs of antibody-PROTACCC BY · PubMed Central
Fig. 83 The representative PROTACs of aptamer-PROTAC conjugates
Fig. 83 The representative PROTACs of aptamer-PROTAC conjugatesCC BY · PubMed Central
Fig. 84 The representative PROTAC of dual-target PROTACs
Fig. 84 The representative PROTAC of dual-target PROTACsCC BY · PubMed Central
Fig. 85 The representative PROTACs of Folate-Caged PROTACs
Fig. 85 The representative PROTACs of Folate-Caged PROTACsCC BY · PubMed Central
Fig. 86 The representative PROTACs of TF-PROTACS
Fig. 86 The representative PROTACs of TF-PROTACSCC BY · PubMed Central

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Citations

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Research works printed but not linked: 5

  1. Georg, E. W. et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015). · DOI · Paper page
  2. Yang, C. et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 36, 2255–2264 (2016). · DOI
  3. Zhou, B. et al. Discovery of a small-molecule degrader of bromodomain and extra-terminal(BET) proteins with picomolar cellular potencies and capable of achieving tumor regression. J. Med. Chem. 61, 462–481 (2018). · DOI
  4. 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). · DOI · Paper page
  5. Mu, X. P., Bai, L. T., Xu, Y. J., Wang, J. Y. & Lu, H. B. Protein targeting chimeric molecules specific for dual bromodomain 4(BRD4) and Polo-like kinase 1(PLK1) proteins in acute myeloidleukemia cells. Biochem. Biophys. Res. Commun. 521, 833–839 (2019). · DOI

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Metadata

Authors
He, M., Cao, C., Ni, Z., Liu, Y., Song, P., Hao, S., He, Y., Sun, X., & Rao, Y.
Affiliations
  • Tsinghua University (CN)
  • Zhengzhou University (CN)
Corresponding author
Rao, Yu
ORCID
Venue
Signal Transduction and Targeted Therapy
Publisher
Springer Science and Business Media LLC
Published
2022-06-09
Volume
7
Issue
1
Pages
181-181
ISSN
2059-3635 (ISSN-L)
DOI
10.1038/s41392-022-00999-9
PMC
PMC9178337
OpenAlex
W4281795388
Cited by
283
References
559
Citations by year
2026: 50 · 2025: 82 · 2024: 84 · 2023: 50 · 2022: 17
FWCI
6.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (#82125034, #81773567, 2021YFA1302100, 2020YFE0202200)
  • China Postdoctoral Science Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords
PROTACs, protein degradation, bifunctional small molecules, ubiquitination, ubiquitin-proteasome system, molecular glues, small-molecule degraders, clinical development, cancer therapy
MeSH terms
Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Proteolysis

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