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Design, synthesis, and biological evaluation of BRD4 degraders
Mengyuan Ding1, Yingying Shao2, Danwen Sun2
1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, PR China.
Abstract:
Epigenetic proteins are one of the important targets in the current research fields of cancer therapy. A family of bromodomain-containing (BRD) and extra terminal domain (BET) proteins act as epigenetic readers to regulate the expression of key oncogenes and anti-apoptotic proteins. Recently, although BET degraders based on PROTAC technology have achieved significant antitumor effects, the lack of selectivity for BET protein degradation has not been fully addressed. Herein, a series of small molecule BRD4 PROTACs were designed and synthesized. Most of the degraders were effective in inhibiting MM.1S and MV-4-11 cell lines, especially in MV-4-11. Among them, degrader 8b could induce the degradation of BRD4 and exhibited a time- and concentration-dependent depletion manner and there was a significant depletion of BRD4, laying a foundation for effectively treating leukemia and multiple myeloma. Moreover, 8b could also effectively prevent the activation of MRC5 cells by inducing the degradation of BRD4 protein, which preliminarily proves that the BRD4 degrader based on the PROTAC concept has great potential for the treatment of pulmonary fibrosis. Taken together, these findings laid a foundation for BRD4 degraders as an effective strategy for treating related diseases.
Insights
New PROTAC degraders targeting BRD4 show promise for treating leukemia, multiple myeloma, and pulmonary fibrosis by selectively degrading key proteins involved in cancer and cell activation.
Area of Science:
- Epigenetics
- Molecular Biology
- Drug Discovery
Background:
- Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers regulating oncogene expression.
- BET degraders using PROTAC technology show antitumor effects but lack selectivity.
- Targeting BRD4, a BET protein, is a key strategy in cancer therapy.
Purpose of the Study:
- To design and synthesize novel small molecule BRD4 PROTACs with improved selectivity.
- To evaluate the efficacy of these PROTACs in inhibiting cancer cell lines and preventing cell activation.
Main Methods:
- Design and synthesis of small molecule BRD4 PROTACs.
- In vitro testing of PROTACs on MM.1S and MV-4-11 cell lines.
- Assessment of BRD4 degradation and its time/concentration dependency.
Main Results:
- Several synthesized PROTACs inhibited MM.1S and MV-4-11 cell lines, particularly MV-4-11.
- Degrader 8b effectively induced time- and concentration-dependent BRD4 degradation.
- Degrader 8b showed potential in preventing MRC5 cell activation, suggesting therapeutic applications for pulmonary fibrosis.
Conclusions:
- BRD4 degraders based on PROTAC technology offer a promising strategy for treating leukemia and multiple myeloma.
- BRD4 degraders may also hold potential for treating pulmonary fibrosis.
- These findings establish a foundation for developing targeted BRD4 degradation therapies.
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