Discovery of the GSH responsive "Y-PROTACs" targeting ALK and CDK4/6 as a potential treatment for cancer

作者全名："Wang, Shirui; Luo, Dan; Pu, Chunlan; Ma, Xinyu; Zhang, Hongjia; Feng, Zhanzhan; Deng, Rui; Yu, Su; Liu, Yuanyuan; Huang, Qing; Li, Rui"

作者地址："[Wang, Shirui; Luo, Dan; Ma, Xinyu; Zhang, Hongjia; Feng, Zhanzhan; Deng, Rui; Yu, Su; Liu, Yuanyuan; Huang, Qing; Li, Rui] Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy, Chengdu 610031, Peoples R China; [Wang, Shirui; Luo, Dan; Ma, Xinyu; Zhang, Hongjia; Feng, Zhanzhan; Deng, Rui; Yu, Su; Liu, Yuanyuan; Huang, Qing; Li, Rui] Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610031, Peoples R China; [Luo, Dan] Sichuan Univ, West China Hosp, Dept Pharm, Chengdu 610031, Peoples R China; [Pu, Chunlan] Chongqing Med Univ, Southwest Jiaotong Univ, Peoples Hosp Chengdu 3, Chengdu Hosp 2,Affiliated Hosp,Med Res Ctr, Chengdu 610031, Peoples R China; [Ma, Xinyu] Univ Groningen, Groningen Res Inst Pharm, Dept Nanomed & Drug Targeting, NL-9713 AV Groningen, Netherlands"

通信作者："Li, R (通讯作者)，Sichuan Univ, West China Hosp, Collaborat Innovat Ctr Biotherapy, State Key Lab Biotherapy, Chengdu 610031, Peoples R China.; Li, R (通讯作者)，Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610031, Peoples R China."

来源：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:000923095100001

JCR分区：Q1

影响因子：6.7

年份：2023

卷号：248

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：GSH responsive ?Y-PROTACs?; Tumor cell targeting; ALK degradation; CDK4; 6 inhibition; Dual degradation

摘要："Combination of different molecular target inhibitors is an available method to improve the therapeutic effect on tumors. Herein, to achieve both tumor cell targeting and ALK degradation & CDK4/6 inhibition in one molecule, we designed and synthesized a novel GSH responsive ""Y-PROTACs"", Y5-3, a highly potent molecule with an IC50 value of 90 nM against H3122 cells, which can be cleaved into ALK PROTAC and CDK4/6 inhibitor moieties in tumor cells. Mechanism studies revealed that Y5-3 exert anti-tumor proliferation activity in vitro not only by ALK degradation and CDK4/6 inhibition, but also by ALK/CDK4 dual degradation. These properties make Y5-3 a GSH responsive multifunctional antitumor agent, and our work provide a new strategy for the development of multifunctional PROTACs."

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

基金资助正文："Acknowledgments This work was supported by the National Natural Science Foundation of China (81773195) , the Sichuan Science and Technology Program 2021YJ0220 and the Technology Innovation Research and Development Project of Chengdu (No. 2022-YF05-01982-SN) . The Analytical & Testing Center of Sichuan University is gratefully acknowledged for the characterization of the new compounds."