Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation

作者全名：Wang, Shirui; Feng, Zhanzhan; Qu, Can; Yu, Su; Zhang, Hongjia; Deng, Rui; Luo, Dan; Pu, Chunlan; Zhang, Yan; Li, Rui

作者地址：[Wang, Shirui; Feng, Zhanzhan; Yu, Su; Zhang, Hongjia; Deng, Rui; Li, Rui] Sichuan Univ, West China Hosp, Canc Ctr, Dept Biotherapy, Chengdu 610041, Peoples R China; [Wang, Shirui; Feng, Zhanzhan; Yu, Su; Zhang, Hongjia; Deng, Rui; Li, Rui] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China; [Qu, Can] Chengdu Univ Tradit Chinese Med, Sch Pharm, State Key Lab Southwestern Chinese Med Resources, Chengdu 611137, Peoples R China; [Luo, Dan] Sichuan Univ, West China Hosp, Dept Pharm, Chengdu 610031, Peoples R China; [Pu, Chunlan] Southwest Jiaotong Univ, Chongqing Med Univ, Peoples Hosp Chengdu 3, Med Res Ctr,Affiliated Hosp,Chengdu Hosp 2, Chengdu 610031, Peoples R China; [Zhang, Yan] Sichuan Univ, West China Hosp, Canc Ctr, Dept Med Oncol, Chengdu 610041, Sichuan, Peoples R China; [Zhang, Yan] Sichuan Univ, West China Hosp, Lung Canc Inst, Lung Canc Ctr, Chengdu 610041, Sichuan, Peoples R China

通信作者：Li, R (通讯作者)，Sichuan Univ, West China Hosp, Canc Ctr, Dept Biotherapy, Chengdu 610041, Peoples R China.; Li, R (通讯作者)，Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.; Zhang, Y (通讯作者)，Sichuan Univ, West China Hosp, Canc Ctr, Dept Med Oncol, Chengdu 610041, Sichuan, Peoples R China.; Zhang, Y (通讯作者)，Sichuan Univ, West China Hosp, Lung Canc Inst, Lung Canc Ctr, Chengdu 610041, Sichuan, Peoples R China.

来源：JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:001242781000001

JCR分区：Q1

影响因子：6.8

年份：2024

卷号：67

期号：12

开始页：9842

结束页：9856

文献类型：Article

关键词：　

摘要：Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, B1-PEG, synthesized through PEGylation of an optimized PROTAC molecule, B1, to enhance its properties. B1-PEG is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed B1-PEG's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule B1. When tested in a H3122 xenograft mouse model, B1-PEG significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.

基金机构：National Natural Science Foundation of China [81773195, 82303606]; National Natural Science Foundation of China [2021YJ0220, 2023YFH0097]; Sichuan Science and Technology Program [2021CDDZ-26]; Dazhou Sichuan University project of Dazhou Bureau Science and Technology

基金资助正文：This work was supported by the National Natural Science Foundation of China (No. 81773195, No.82303606), Sichuan Science and Technology Program (No. 2021YJ0220, No. 2023YFH0097), Dazhou Sichuan University project of Dazhou Bureau Science and Technology (No. 2021CDDZ-26). The Analytical & Testing Center of Sichuan University is gratefully acknowledged for the characterization of the new compounds.