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Signal Transduct Target Ther. 2019 Dec 24;4:64. doi: 10.1038/s41392-019-0101-6. eCollection 2019.

PROTACs: great opportunities for academia and industry.

Sun X1,2, Gao H1,2, Yang Y1,2, He M1, Wu Y1, Song Y1, Tong Y1, Rao Y1,3.

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

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.

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