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.
- 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: [email protected].
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.