机构：[1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.四川大学华西医院[2]State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.[3]Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610031, China.四川大学华西医院[4]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.[5]Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[6]Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院
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：
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).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2024]版：
无
最新[2023]版：
大类|1 区医学
小类|1 区药物化学
第一作者：
第一作者机构：[1]Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
共同第一作者：
通讯作者：
通讯机构：[5]Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.[6]Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
推荐引用方式(GB/T 7714)：
Wang Shirui,Feng Zhanzhan,Qu Can,et al.Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation[J].Journal Of Medicinal Chemistry.2024,doi:10.1021/acs.jmedchem.3c02340.
APA：
Wang Shirui,Feng Zhanzhan,Qu Can,Yu Su,Zhang Hongjia...&Li Rui.(2024).Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation.Journal Of Medicinal Chemistry,,
MLA：
Wang Shirui,et al."Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation".Journal Of Medicinal Chemistry .(2024)
医学