2024-11-11 カリフォルニア大学リバーサイド校(UCR)
<関連情報>
- https://news.ucr.edu/articles/2024/11/11/protein-degradation-strategy-offers-hope-cancer-therapy
- https://www.pnas.org/doi/10.1073/pnas.2403330121
タンパク質不安定化化合物によるPin1の標的分解 Targeted degradation of Pin1 by protein-destabilizing compounds
Giulia Alboreggia, Parima Udompholkul, Isaac Rodriguez, +1, and Maurizio Pellecchia
Proceedings of the National Academy of Sciences Published:November 12, 2024
DOI:https://doi.org/10.1073/pnas.2403330121
Significance
Our studies propose a ligand design strategy based on the selection of potent protein binders that can also induce target instability in vitro. In turn, those agents cause target degradation in cell. Application of this strategy to the proline cis–trans isomerase Pin1 resulted in potent compounds that are effective in causing Pin1 degradation in several human cancer cell lines and that can be translated into potential anticancer agents. The design strategy of such agents, we term here molecular crowbars, represents an efficient way to induce protein degradation in cell without the need of designing chimeric bidentate agents like in protein targeted chimeras (PROTACs) or molecular glues, hence could find wide applications in pharmacology and drug discovery.
Abstract
The concept of targeted protein degradation is at the forefront of modern drug discovery, which aims to eliminate disease-causing proteins using specific molecules. In this paper, we explored the idea to design protein degraders based on the section of ligands that cause protein destabilization, hence that facilitate the cellular breakdown of the target. Our studies present covalent agents targeting Pin1, a cis–trans prolyl isomerase that plays a crucial role in tumorigenesis. Our design strategy entailed iterative optimizations of agents for potency and Pin1 destabilization in vitro. Biophysical and cellular studies suggest that the agents may act like molecular crowbars, displacing protein-stabilizing interactions that open the structure for recognition by the proteasome degradation machinery. This approach resulted in a series of potent and effective Pin1 degraders with potential applications in target validation and in therapeutic development. We propose that our design strategy can identify molecular degraders without engineering bifunctional agents that artificially create interactions between a disease-causing protein and a ubiquitin ligase.
