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Published on: November 9, 2020
Structure-guided discovery of novel potent and efficacious proteolysis targeting chimera (PROTAC) degrader of BRD4
Wang Xiang1, Qiwei Wang1, Kai Ran1
1State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
Abstract:
Bromodomain-containing protein 4 (BRD4) has been identified as a potential target in the treatment of many cancers and several BRD4 inhibitors have entered clinical studies. Previous studies have shown that BRD4 degraders have potential to overcome resistance to BRD4 inhibitors. However, most of the BRD4 degraders have poor solubility and bioavailability, one of which the reason is large molecular weight. Here, we describe the design, synthesis, and evaluation studies of a BRD4 degrader based on the proteolysis targeting chimeras (PROTAC) concept. Our efforts have led to the discovery of compound 15, which is a weak inhibitor and potent BRD4 degrader with a molecular weight of 821.8. In vitro, 15 can completely degrade BRD4 at nanomolar concentration, with DC50 = 0.25 and 3.15 nM in MV4-11 and RS4-11 cell lines, respectively. Further optimization of compound 15 may reduce its molecular weight and improve druggabillity, and provide a new choice for the treatment of cancer.
Insights
Researchers developed a novel bromodomain-containing protein 4 (BRD4) degrader using proteolysis targeting chimeras (PROTAC) technology. This compound effectively degrades BRD4 in cancer cells, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Bromodomain-containing protein 4 (BRD4) is a validated target for cancer therapy.
- BRD4 inhibitors show clinical promise, but resistance can emerge.
- BRD4 degraders offer a strategy to overcome resistance to inhibitors.
Purpose of the Study:
- To design, synthesize, and evaluate novel BRD4 degraders.
- To address limitations of existing BRD4 degraders, such as poor solubility and bioavailability due to large molecular weight.
- To discover a potent and effective BRD4 degrader using the PROTAC concept.
Main Methods:
- Proteolysis targeting chimeras (PROTAC) technology was employed for molecular design.
- Synthesis and chemical characterization of novel compounds.
- In vitro evaluation of BRD4 degradation in cancer cell lines (MV4-11 and RS4-11).
Main Results:
- Compound 15, a novel BRD4 degrader, was discovered.
- Compound 15 exhibits potent BRD4 degradation at nanomolar concentrations (DC50 = 0.25 nM in MV4-11, 3.15 nM in RS4-11).
- Compound 15 is a weak inhibitor but a potent degrader of BRD4.
Conclusions:
- Compound 15 represents a promising BRD4 degrader with potential for cancer treatment.
- Further optimization could reduce molecular weight and enhance druggability.
- This PROTAC-based approach offers a new therapeutic avenue for cancers targeting BRD4.
