Review

. 2022 Jun 9;7(1):181.

doi: 10.1038/s41392-022-00999-9.

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

Ming He^#¹, Chaoguo Cao^#^{1

2}, Zhihao Ni^#¹, Yongbo Liu¹, Peilu Song¹, Shuang Hao¹, Yuna He¹, Xiuyun Sun¹, Yu Rao^{3

4}

Affiliations

¹ Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 100084, Beijing, P. R. China.
² Tsinghua-Peking Center for Life Sciences, 100084, Beijing, P. R. China.
³ Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 100084, Beijing, P. R. China. yrao@tsinghua.edu.cn.
⁴ School of Pharmaceutical Sciences, Zhengzhou University, 450001, Zhengzhou, China. yrao@tsinghua.edu.cn.

^# Contributed equally.

PMID: 35680848
PMCID: PMC9178337
DOI: 10.1038/s41392-022-00999-9

Review

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

Ming He et al. Signal Transduct Target Ther. 2022.

. 2022 Jun 9;7(1):181.

doi: 10.1038/s41392-022-00999-9.

Authors

Ming He^#¹, Chaoguo Cao^#^{1

2}, Zhihao Ni^#¹, Yongbo Liu¹, Peilu Song¹, Shuang Hao¹, Yuna He¹, Xiuyun Sun¹, Yu Rao^{3

4}

Affiliations

¹ Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 100084, Beijing, P. R. China.
² Tsinghua-Peking Center for Life Sciences, 100084, Beijing, P. R. China.
³ Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, 100084, Beijing, P. R. China. yrao@tsinghua.edu.cn.
⁴ School of Pharmaceutical Sciences, Zhengzhou University, 450001, Zhengzhou, China. yrao@tsinghua.edu.cn.

^# Contributed equally.

PMID: 35680848
PMCID: PMC9178337
DOI: 10.1038/s41392-022-00999-9

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1**
The mechanism of PROTAC-mediated protein degradation

**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. 3**
The list of human “degradable” kinases based on PROTAC

**Fig. 4**
The representative PROTACs targeting AR

**Fig. 5**
The representative PROTACs targeting BRAF and BRAF^V600E

**Fig. 6**
The representative PROTAC targeting eEF2K

**Fig. 7**
The representative PROTACs targeting EGFR

**Fig. 8**
The representative PROTACs targeting eIF4E

**Fig. 9**
The representative PROTACs targeting ER

**Fig. 10**
The representative PROTAC targeting FGFR1/2

**Fig. 11**
The representative PROTACs targeting IGF-1R and Src

**Fig. 12**
The representative PROTACs targeting KRAS^G12C

**Fig. 13**
The representative PROTACs targeting MEK

**Fig. 14**
The representative PROTAC targeting Myc

**Fig. 15**
The representative PROTACs targeting p38

**Fig. 16**
The representative PROTACs targeting PDEδ

**Fig. 17**
The representative PROTACs targeting SHP2

**Fig. 18**
The representative PROTACs targeting AKT

**Fig. 19**
The representative PROTACs targeting ALK

**Fig. 20**
The representative PROTACs targeting Bcl-xl

**Fig. 21**
The representative PROTACs targeting BCR-ABL

**Fig. 22**
The representative PROTACs targeting FAK

**Fig. 23**
The representative PROTACs targeting MDM2

**Fig. 24**
The representative PROTACs targeting FLT3

**Fig. 25**
The representative PROTACs targeting JAK

**Fig. 26**
The representative PROTAC targeting STAT3

**Fig. 27**
The representative PROTAC targeting β-catenin

**Fig. 28**
The representative PROTAC targeting FOXM1

**Fig. 29**
The representative PROTAC targeting α_1A-AR

**Fig. 30**
The representative PROTACs targeting BRD

**Fig. 31**
The representative PROTAC targeting CBP and p300

**Fig. 32**
The representative PROTAC targeting ENL

**Fig. 33**
The representative PROTACs targeting HDAC

**Fig. 34**
The representative PROTAC targeting KDM5C

**Fig. 35**
The representative PROTAC targeting NAMPT

**Fig. 36**
The representative PROTAC targeting NSD3

**Fig. 37**
The representative PROTACs targeting PRC2 (EZH2, EED)

**Fig. 38**
The representative PROTAC targeting PRMT5

**Fig. 39**
The representative PROTAC targeting SIRT2

**Fig. 40**
The representative PROTACs targeting WDR5

**Fig. 41**
The representative PROTACs targeting Aurora A

**Fig. 42**
The representative PROTAC targeting Cdc20

**Fig. 43**
The representative PROTACs targeting CDK2

**Fig. 44**
The representative PROTAC targeting CDK2/5

**Fig. 45**
The representative PROTACs targeting CDK2/4/6

**Fig. 46**
The representative PROTACs targeting CDK9

**Fig. 47**
The representative PROTACs targeting CDK12

**Fig. 48**
The representative PROTAC targeting Wee1

**Fig. 49**
The representative PROTACs targeting CRBN

**Fig. 50**
The representative PROTAC targeting hRpn13^Pru

**Fig. 51**
The representative PROTAC targeting VHL

**Fig. 52**
The representative PROTAC targeting ZFP91

**Fig. 53**
The representative PROTACs targeting BTK

**Fig. 54**
The representative PROTAC targeting CCR9

**Fig. 55**
The representative PROTAC targeting CD147

**Fig. 56**
The representative PROTAC targeting CRABP

**Fig. 57**
The representative PROTAC targeting HSP90

**Fig. 58**
The representative PROTAC targeting IDO1

**Fig. 59**
The representative PROTAC targeting LXR-β

**Fig. 60**
The representative PROTAC targeting MIF

**Fig. 61**
The representative PROTACs targeting PARP1

**Fig. 62**
The representative PROTAC targeting PARP14

**Fig. 63**
The representative PROTACs targeting PD-L1

**Fig. 64**
The representative PROTAC targeting PLK1

**Fig. 65**
The representative PROTAC targeting RAR

**Fig. 66**
The representative PROTAC targeting RHAU

**Fig. 67**
The representative PROTAC targeting RIPK2

**Fig. 68**
The representative PROTAC targeting SF3B1

**Fig. 69**
The representative PROTAC targeting SLC

**Fig. 70**
The representative PROTACs targeting SMARCA2/4

**Fig. 71**
The representative PROTAC targeting SRC-1

**Fig. 72**
The representative PROTAC targeting tyrosinase

**Fig. 73**
The representative PROTACs targeting pan-coronavirus antiviral

**Fig. 74**
The representative PROTACs targeting SARS-CoV-2

**Fig. 75**
The representative PROTACs targeting HDAC3

**Fig. 76**
The representative PROTACs targeting H-PGDS

**Fig. 77**
The representative PROTAC targeting IRAK1

**Fig. 78**
The representative PROTAC targeting IRAK3

**Fig. 79**
The representative PROTACs targeting IRAK4

**Fig. 80**
The representative PROTACs targeting neurodegenerative diseases

**Fig. 81**
The representative PROTACs targeting Cas protein, HMGCR and VEGFR2

**Fig. 82**
The representative PROTACs of antibody-PROTAC

**Fig. 83**
The representative PROTACs of aptamer-PROTAC conjugates

**Fig. 84**
The representative PROTAC of dual-target PROTACs

**Fig. 85**
The representative PROTACs of Folate-Caged PROTACs

**Fig. 86**
The representative PROTACs of TF-PROTACS

See this image and copyright information in PMC

References

1. Sakamoto KM, et al. PROTACs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl Acad. Sci. USA. 2001;98:8554–8559. doi: 10.1073/pnas.141230798. - DOI - PMC - PubMed
1. Winter GE, et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015;348:1376–1381. doi: 10.1126/science.aab1433. - DOI - PMC - PubMed
1. Neklesa TK, et al. ARV-110: an androgen receptor PROTAC degrader for prostate cancer. Am. Assoc. Cancer Res. 2018;78:5236.
1. Neklesa, T. K. et al. ARV-110: an oral androgen receptor PROTAC degrader for prostate cancer. J. Clin. Oncol.37, 14–16 (2019).
1. Halford B. Arvinas unveils PROTAC structures. Chem. Eng. N. 2021;99:5.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous