2024-05-13 ゲーテ大学
<関連情報>
- https://aktuelles.uni-frankfurt.de/english/derivatives-of-the-thalidomide-compound-drive-resistant-cancer-cells-to-their-deaths/
- https://www.cell.com/cell-reports-physical-science/fulltext/S2666-3864(24)00220-0
サリドマイド誘導体はCRBNの結合表面を再プログラムすることによってBCL-2を分解する Thalidomide derivatives degrade BCL-2 by reprogramming the binding surface of CRBN
Jianhui Wang (王建辉),Marcel Heinz,…,Kang Han (韩康),Jun Zhou (周俊),Ivan Dikic,Xinlai Cheng (承辛来)
Cell Reports Physical Science Published:May 02, 2024
DOI:https://doi.org/10.1016/j.xcrp.2024.101960
Highlights
- Thalidomide derivatives are identified as BCL-2 degraders
- AlphaFold predicts GLY128, ALA131, and THR132 are key in the binding
- Derivatives degrade venetoclax-resistant BCL-2 mutations
- Survival is boosted in Drosophila tumor model
Summary
Recent studies demonstrate that modified thalidomide chemically alters the binding surface of its binding E3 ligase, CRBN, leading to the degradation of new substrate proteins. In this study, we conduct a proteome-wide analysis of thalidomide-like compounds and pinpoint three derivatives (C5, C6, and C7) that specifically target and degrade the BCL-2 protein. Using AlphaFold-driven molecular modeling combined with experimental data, we suggest that GLY128, ALA131, and THR132 are crucial in forming a CRBN-C5-BCL-2 ternary complex. This interaction is notably distinct from that of venetoclax, a known clinical BCL-2 inhibitor that interacts with the BH3 domain. Significantly, these thalidomide derivatives have the ability to degrade BCL-2 mutations that are resistant to venetoclax, thereby enhancing survival rates in a Notch-depleted Drosophila intestinal tumor model. Our findings highlight the critical role of targeted modifications to the E3 ligase surface in altering its binding affinity and achieving a new substrate protein profile.
Graphical abstract
