Current strategies for improving limitations of proteolysis targeting chimeras

作者全名："Pu, Chunlan; Wang, Shirui; Liu, Lei; Feng, Zhonghui; Zhang, Hongjia; Gong, Qianyuan; Sun, Yueshan; Guo, Yuanbiao; Li, Rui"

作者地址："[Pu, Chunlan; Liu, Lei; Feng, Zhonghui; Gong, Qianyuan; Sun, Yueshan; Guo, Yuanbiao] Southwest Jiaotong Univ, Chongqing Med Univ, Chengdu Hosp 2, Med Res Ctr,Affiliated Hosp,Peoples Hosp Chengdu 3, Chengdu 610031, Peoples R China; [Wang, Shirui; Zhang, Hongjia; Li, Rui] West China Hosp, State Key Lab Biotherapy, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China; [Wang, Shirui; Zhang, Hongjia; Li, Rui] Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Peoples R China"

通信作者："Guo, YB (通讯作者)，Southwest Jiaotong Univ, Chongqing Med Univ, Chengdu Hosp 2, Med Res Ctr,Affiliated Hosp,Peoples Hosp Chengdu 3, Chengdu 610031, Peoples R China.; Li, R (通讯作者)，West China Hosp, State Key Lab Biotherapy, Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China.; Li, R (通讯作者)，Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Peoples R China."

来源：CHINESE CHEMICAL LETTERS

ESI学科分类：CHEMISTRY

WOS号：WOS:000995373300001

JCR分区：Q1

影响因子：9.4

年份：2023

卷号：34

期号：6

开始页：　

结束页：　

文献类型：Article

关键词：PROTACs; Targeted protein degradation; Oral bioavailability; Cell permeability; Tumor targeting

摘要："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.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences."

基金机构：National Natural Science Foundation of China [81773195]; Sichuan Science and Tech- nology Program [2021YJ0220]; Technology Innovation Research and Development Project of Chengdu [2022-YF05 -01982]; Foundation of Science and Technology Department of Sichuan Province [2022YFS0172]

基金资助正文："We thank all members for the writing and development of this review. This work was supported by National Natural Science Foundation of China (No. 81773195) , Sichuan Science and Tech- nology Program (No. 2021YJ0220) , Technology Innovation Research and Development Project of Chengdu (No. 2022-YF05 -01982-SN) , the Foundation of Science and Technology Department of Sichuan Province (No. 2022YFS0172) ."