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Review
. 2020 May 13;13(1):50.
doi: 10.1186/s13045-020-00885-3.

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Xin Li  1 , Yongcheng Song  2   3
Affiliations
Review

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

Xin Li et al. J Hematol Oncol. .

Abstract

Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.

Keywords: Cancer therapy; Hematological malignancies; PROTAC; Targeted protein degradation.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a Mechanism of PROTAC-mediated protein degradation. b Representative small-molecule ligands of E3s used for PROTAC. c Timeline and major milestones for the development of PROTAC
Fig. 2
Fig. 2
a Common ligands of BRD4. b Structures and biological activities of PROTACs targeting BRD4. Structures of the E3 ligands are shown in Fig. 1
Fig. 3
Fig. 3
Structures and biological activities of PROTACs targeting BTK
Fig. 4
Fig. 4
Structures and biological activities of PROTACs targeting BCR-ABL
Fig. 5
Fig. 5
Structures and biological activities of PROTACs targeting MCL1
Fig. 6
Fig. 6
Structures and biological activities of PROTACs targeting FLT-3
Fig. 7
Fig. 7
Structure and biological activities of PROTAC targeting STAT3
Fig. 8
Fig. 8
Structure and biological activities of PROTAC targeting BAF
See this image and copyright information in PMC

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