Selective degradation of cellular BRD3 and BRD4-L promoted by PROTAC molecules in six cancer cell lines

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Targeted protein degradation using PROTACs is a key strategy in cancer therapy.
• Selective degradation of BET family proteins, specifically BRD3 and BRD4-L, presents a significant challenge.

Purpose of the Study:

• To develop and characterize a novel PROTAC molecule for selective degradation of BRD3 and BRD4-L.
• To evaluate the efficacy of this selective degradation strategy in cancer cell lines and an animal model.

Main Methods:

• Design and synthesis of a novel PROTAC molecule (compound 24).
• Assessment of protein degradation selectivity across BET family members (BRD2, BRD3, BRD4-S, BRD4-L) in six cancer cell lines.
• In vivo efficacy study using a mouse xenograft model with an optimized compound (28).

Main Results:

• Compound 24 selectively degraded BRD3 and BRD4-L, but not BRD2 or BRD4-S, in various cancer cell lines.
• Target selectivity was influenced by protein degradation kinetics and cell line type.
• Optimized compound 28 demonstrated in vivo selective degradation of BRD3 and BRD4-L, leading to robust antitumor activity in a mouse xenograft model.

Conclusions:

• Selective degradation of BRD3 and BRD4-L over BRD2 and BRD4-S is achievable and effective in multiple cancer contexts.
• This approach holds potential for advancing cancer research and developing new therapeutics targeting BRD3 and BRD4-L.