Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 4, 64
eCollection

PROTACs: Great Opportunities for Academia and Industry

Affiliations
Review

PROTACs: Great Opportunities for Academia and Industry

Xiuyun Sun et al. Signal Transduct Target Ther.

Abstract

Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

Keywords: Chemical biology; Drug discovery.

Conflict of interest statement

Competing interestsThe authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Mode of action of PROTACs.
Fig. 2
Fig. 2
Comparisons of PROTACs with other therapeutic modalities.
Fig. 3
Fig. 3
Publications on PROTACs in recent years.
Fig. 4
Fig. 4. Distribution of PROTACs.
a Efficacy of PROTACs in different diseases. b Efficacy of PROTACs in different biological processes.
Fig. 5
Fig. 5
Representative PROTAC of AHR.
Fig. 6
Fig. 6
Representative PROTACs of ALK.
Fig. 7
Fig. 7
Representative PROTACs degrading drug-resistant AR.
Fig. 8
Fig. 8
Representative PROTAC targeting BCL2.
Fig. 9
Fig. 9
Representative PROTAC of BCL6.
Fig. 10
Fig. 10
Representative PROTACs targeting drug-resistant BCR-ABL.
Fig. 11
Fig. 11
Representative PROTACs targeting drug-resistant BET.
Fig. 12
Fig. 12
Representative PROTACs targeting BRD9/7.
Fig. 13
Fig. 13
Representative PROTACs targeting drug-resistant BTK.
Fig. 14
Fig. 14
Representative PROTACs targeting CDK4/6.
Fig. 15
Fig. 15
Chemical structure of the reported CDK8 PROTAC.
Fig. 16
Fig. 16
Representative PROTACs of CDK9.
Fig. 17
Fig. 17
Representative PROTAC targeting CK2.
Fig. 18
Fig. 18
Representative PROTACs of c-Met.
Fig. 19
Fig. 19
Representative PROTACs of DHODH.
Fig. 20
Fig. 20
Potency of EGFR PROTACs in different cell lines.
Fig. 21
Fig. 21
Representative PROTACs of EGFR and HER2.
Fig. 22
Fig. 22
Representative PROTAC of eIF4E.
Fig. 23
Fig. 23
Representative PROTACs targeting drug-resistant ER.
Fig. 24
Fig. 24
Representative PROTACs of ERK1 and ERK2.
Fig. 25
Fig. 25
Representative PROTACs targeting ERRα.
Fig. 26
Fig. 26
Representative PROTACs of FAK.
Fig. 27
Fig. 27
Representative PROTACs of FLT3.
Fig. 28
Fig. 28
Representative PROTACs of HDAC6.
Fig. 29
Fig. 29
Representative PROTACs targeting MCL1.
Fig. 30
Fig. 30
Chemical structures of the reported MDM2 inhibitor and PROTACs.
Fig. 31
Fig. 31
Representative PROTACs of p38α and p38δ.
Fig. 32
Fig. 32
Representative PROTAC of PARP1.
Fig. 33
Fig. 33
Representative PROTAC of PI3K.
Fig. 34
Fig. 34
Representative PROTAC of pirin.
Fig. 35
Fig. 35
Representative PROTAC of PRC2.
Fig. 36
Fig. 36
Representative PROTAC of RIPK2.
Fig. 37
Fig. 37
Representative PROTAC of Rpn13.
Fig. 38
Fig. 38
Representative PROTAC of SGK-3.
Fig. 39
Fig. 39
Representative PROTAC of Smad3.
Fig. 40
Fig. 40
Representative PROTAC of STAT3.
Fig. 41
Fig. 41
Representative PROTAC of TBK1.
Fig. 42
Fig. 42
Representative PROTAC targeting TRIM 24.
Fig. 43
Fig. 43
Representative PROTAC targeting NS3.
Fig. 44
Fig. 44
Representative PROTAC of IRAK4.
Fig. 45
Fig. 45
Representative PROTAC of PCAF/GCN5.
Fig. 46
Fig. 46
Representative PROTAC of Sirt2.
Fig. 47
Fig. 47
Representative PROTAC of Tau.
Fig. 48
Fig. 48
Representative PROTACs of FKBP12.

Similar articles

See all similar articles

References

    1. Toure M, Crews CM. Small-molecule PROTACS: new approaches to protein degradation. Angew. Chem. Int Ed. Engl. 2016;55:1966–1973. doi: 10.1002/anie.201507978. - DOI - PubMed
    1. Zou Y, Ma D, Wang Y, Zou Y. The PROTAC technology in drug development. Cell Biochem. Funct. 2019;37:21–30. doi: 10.1002/cbf.3369. - DOI - PMC - PubMed
    1. Yang C-Y, Qin C, Bai L, Wang S. Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins - A review. Drug Discov. Today Technol. 2019;31:43–51. doi: 10.1016/j.ddtec.2019.04.001. - DOI - PubMed
    1. Wurz RP, Cee VJ. Targeted degradation of MDM2 as a new approach to improve the efficacy of MDM2-p53 inhibitors. J. Med. Chem. 2019;62:445–447. doi: 10.1021/acs.jmedchem.8b01945. - DOI - PubMed
    1. Watt GF, Scott-Stevens P, Gaohua L. Targeted protein degradation in vivo with proteolysis targeting chimeras: current status and future considerations. Drug Discov. Today Technol. 2019;31:69–80. doi: 10.1016/j.ddtec.2019.02.005. - DOI - PubMed

LinkOut - more resources

Feedback