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

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机构： [1]State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610031, China [2]Department of Pharmacy, West China Hospital of Sichuan University, Chengdu, 610031, China [3]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 [4]Department of Nanomedicine & Drug Targeting, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV, Groningen, the Netherlands

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关键词： GSH responsive “Y-PROTACs” Tumor cell targeting ALK degradation CDK4/6 inhibition Dual degradation

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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.Copyright © 2023 Elsevier Masson SAS. All rights reserved.

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出版当年[2023]版：

大类 | 2 区

医学

小类 | 1 区药物化学

最新[2023]版：

大类 | 2 区

医学

小类 | 1 区药物化学

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第一作者机构： [1]State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610031, China

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

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