Development of hydrophobic tag-based protein degraders for Bcl-2/Mcl-1 ubiquitination degradation
10.16438/j.0513-4870.2024-0659
- VernacularTitle:基于疏水标签的Bcl-2/Mcl-1蛋白泛素化降解剂
- Author:
Zhe-ming WANG
;
Yi-tong LI
;
Zi-qian WANG
;
Zhi-chao ZHANG
- Publication Type:Research Article
- Keywords:
hydrophobic tag-based protein degrader;
ubiquitination degradation;
Bcl-2 family protein;
anti-cancer
- From:
Acta Pharmaceutica Sinica
2024;59(11):2990-2996
- CountryChina
- Language:Chinese
-
Abstract:
The anti-apoptotic members of Bcl-2 family proteins, Bcl-2 and Mcl-1, are considered therapeutic targets of various cancers. In this article, we developed four hydrophobic tag (HyT)-based protein degraders of Bcl-2/Mcl-1, based on a Bcl-2/Mcl-1 dual inhibitor S1-6, and tested their capability in Bcl-2/Mcl-1 degradation and apoptotic induction in MCF-7 cells. Interestingly, different linkers in the HyT degraders led to selective Bcl-2/Mcl-1 degradation, though the degraders S1-D1-S1-D4 maintained the pan-Bcl-2 family binding capacity. Among them, S1-D2 and S1-D4, two compounds bearing a hydrophobic linker or a PEG linker, were observed to potently and selectively induce the ubiquitination and proteasomal degradation of Bcl-2 and Mcl-1 in living cells, with a degradation rate of more than 80% or 60%, respectively. Moreover, the HyT-based degraders showed increased lethality of cancer cells compared to the parent inhibitor S1-6, demonstrating that the advantage of degraders to the occupancy-based inhibitors.
