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Published on: May 15, 2019
Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders
Rui Yang1, Betsy Pray2, Lapo Alinari2
1Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
Abstract:
Transducin β-like protein 1 X-linked (TBL1X) is an essential scaffold protein involved in multiple signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Recent studies, however, suggest that TBL1X might modulate Wnt-regulated genes independently of β-catenin in diffuse large B-cell lymphoma (DLBCL). Here, we developed selective TBL1X degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy as a proof-of-concept. Eight PROTACs showed strong cytotoxic activity. Interestingly, N-linked PROTACs exhibited minimal TBL1X degradation, while most O-linked PROTACs significantly reduced TBL1X levels, suggesting the crucial role of the linker attachment site in successful TBL1X degradation. Our mechanistic study revealed that TBL1X degradation induced by TD11 relied on the formation of the ternary complex and was dependent on the proteasome. The TBL1X degraders developed in this study could be a valuable chemical tool for investigating TBL1X-related pathways.
Insights
Researchers developed targeted protein degraders (PROTACs) to selectively degrade Transducin β-like protein 1 X-linked (TBL1X) in diffuse large B-cell lymphoma (DLBCL). This novel approach shows promise for investigating TBL1X-related pathways and potential therapeutic strategies.
Area of Science:
- Molecular Biology
- Oncology
- Chemical Biology
Background:
- Transducin β-like protein 1 X-linked (TBL1X) is a key scaffold protein in signaling pathways, including Wnt/β-catenin.
- TBL1X influences β-catenin stability and may regulate Wnt-dependent genes independently in diffuse large B-cell lymphoma (DLBCL).
Purpose of the Study:
- To develop selective TBL1X degraders using Proteolysis Targeting Chimeras (PROTACs) as a proof-of-concept for DLBCL.
- To investigate the mechanism of TBL1X degradation and identify factors influencing PROTAC efficacy.
Main Methods:
- Development of eight PROTACs targeting TBL1X.
- Assessment of cytotoxic activity and TBL1X degradation in DLBCL models.
- Mechanistic studies involving ternary complex formation and proteasomal dependency.
Main Results:
- Eight PROTACs demonstrated significant cytotoxic activity against DLBCL cells.
- O-linked PROTACs were more effective in degrading TBL1X compared to N-linked PROTACs, highlighting the importance of linker attachment site.
- TBL1X degradation by the PROTAC TD11 was confirmed to be proteasome-dependent and involved ternary complex formation.
Conclusions:
- Selective TBL1X degraders were successfully developed using the PROTAC strategy.
- The study underscores the critical role of linker design in PROTAC efficacy for TBL1X degradation.
- These TBL1X degraders represent valuable chemical tools for further research into TBL1X-mediated pathways in DLBCL and beyond.
