PROTAC-Mediated Degradation of TAF1 Induces Apoptosis in AML Cells and Inhibits Tumor Growth In Vivo
Lihong Chen1, Zachary P Shultz2, Marianna Sansone1
1Molecular Oncology Department, Moffitt Cancer Center, Tampa, Florida.
Abstract:
The bromodomain-containing protein, transcription factor IID subunit 1 (TAF1; transcription factor II-250), is the largest component of the multiprotein assembly transcription factor IID, a dynamic complex that serves as a general factor for transcription initiation. CRISPR and RNAi screens of pan-cancer cell lines revealed that TAF1 is broadly required for optimal cell growth and survival, but a subset of cell lines showed enhanced TAF1 dependence. These observations suggest that TAF1 has the potential to serve as a therapeutic target in sensitive tumors. Current approaches employed to target TAF1 are limited to monovalent small-molecule inhibitors of the bromodomain. However, recent studies showed that such inhibitors lack cancer cell kill potential. We applied a structure-guided approach to generate cereblon recruiting Proteolysis Targeting Chimera (PROTAC) degraders of TAF1 using the chemical scaffolds of ceralasertib and GNE371. We present evidence that GNE371-based PROTACs are effective in degradation of TAF1 at concentrations as low as 1 nmol/L. TAF1 depletion activated p53 and induced apoptosis in acute myeloid leukemia (AML) cell lines and certain solid tumor cells. An in vivo active TAF1 PROTAC inhibited the growth of AML tumor xenografts. The results showed that inhibition of the bromodomain is not sufficient to inactivate TAF1 functions, whereas a PROTAC approach induces strong biological effects. Furthermore, TAF1 PROTACs have therapeutic potential against AML and other sensitive tumors.
Insights
New Proteolysis Targeting Chimeras (PROTACs) effectively degrade the TAF1 protein, showing therapeutic potential for acute myeloid leukemia (AML) and other cancers. This approach offers stronger anti-cancer effects than traditional inhibitors.
Area of Science:
- Molecular Biology
- Cancer Therapeutics
- Drug Discovery
Background:
- Transcription factor IID subunit 1 (TAF1) is crucial for transcription initiation and cell survival.
- TAF1 dependence varies across cancer types, suggesting it as a potential therapeutic target.
- Existing TAF1 inhibitors targeting the bromodomain show limited efficacy.
Purpose of the Study:
- To develop novel TAF1 degraders using a PROTAC approach.
- To evaluate the efficacy of TAF1 PROTACs in cancer cell lines and in vivo models.
- To compare the biological effects of PROTACs with traditional bromodomain inhibitors.
Main Methods:
- Structure-guided design of cereblon-recruiting PROTACs targeting TAF1.
- Utilized chemical scaffolds from ceralasertib and GNE371.
- Assessed TAF1 degradation, p53 activation, apoptosis induction, and tumor growth inhibition in AML xenografts.
Main Results:
- GNE371-based PROTACs achieved TAF1 degradation at nanomolar concentrations.
- TAF1 depletion triggered p53 activation and apoptosis in AML and solid tumor cells.
- An in vivo active TAF1 PROTAC significantly inhibited AML tumor xenograft growth.
Conclusions:
- PROTAC-mediated TAF1 degradation is a potent anti-cancer strategy.
- TAF1 PROTACs demonstrate significant therapeutic potential for AML and other cancers.
- Targeting TAF1 degradation offers superior anti-cancer effects compared to bromodomain inhibition alone.
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