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

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

  • Eur J Med Chem. 2023 Feb 15:248:115082. doi: 10.1016/j.ejmech.2022.115082.
Shirui Wang 1,  Dan Luo 2,  Chunlan Pu 3,  Xinyu Ma 4,  Hongjia Zhang 1,  Zhanzhan Feng 1,  Rui Deng 1,  Su Yu 1,  Yuanyuan Liu 1,  Qing Huang 1,  Rui Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610031, China.
  • 2 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610031, China; 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 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610031, China; Department of Nanomedicine & Drug Targeting, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV, Groningen, the Netherlands.
  • 5 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610031, China. Electronic address: lirui@scu.edu.cn.
PMID: 36628851 DOI: 10.1016/j.ejmech.2022.115082
Abstract

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.

Keywords

ALK degradation; CDK4/6 inhibition; Dual degradation; GSH responsive “Y-PROTACs”; Tumor cell targeting.

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