Citation: Chunlan Pu, Shirui Wang, Lei Liu, Zhonghui Feng, Hongjia Zhang, Qianyuan Gong, Yueshan Sun, Yuanbiao Guo, Rui Li. Current strategies for improving limitations of proteolysis targeting chimeras[J]. Chinese Chemical Letters, ;2023, 34(6): 107927. doi: 10.1016/j.cclet.2022.107927 shu

Current strategies for improving limitations of proteolysis targeting chimeras

Chunlan Pu ^a ,
Shirui Wang ^b ,
Lei Liu ^a ,
Zhonghui Feng ^a ,
Hongjia Zhang ^b ,
Qianyuan Gong ^a ,
Yueshan Sun ^a ,
Yuanbiao Guo ^{a, *,} ,
Rui Li ^{b, *,}

a.
Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu 610031, China
b.
State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China

guo.ybiao@yahoo.com

lirui@scu.edu.cn

Received Date: 27 July 2022
Revised Date: 15 October 2022
Accepted Date: 18 October 2022
Available Online: 20 October 2022

Figures(12)

Proteolysis targeting chimeras (PROTACs) are bifunctional degrader molecules via hijacking the ubiquitin-proteasome system (UPS) to specifically eliminate targeted proteins. PROTACs have gained momentum as a new modality of attractive technologies in the drug discovery landscape, since it allows to degrade disease-related proteins effectively. Although some PROTACs drugs reached the clinical research, they are still facing some bottlenecks and challenges that should not be neglected, such as poor oral bioavailability and potential toxic side effects. To overcome these limitations, herein, we provide an overview of recent strategies for improving the durability of PROTACs by enhancing cell permeability and reducing toxic side effects. Meanwhile, the impact of these strategies on improving oral bioavailability as well as their advantages and drawbacks will also be discussed. This review will give a useful reference toolbox for PROTACs design and further promote its clinical application.
- PROTACs,
- Targeted protein degradation,
- Oral bioavailability,
- Cell permeability,
- Tumor targeting
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