Design of Selective BRD4 Inhibitors for the Treatment of Autosomal Dominant Polycystic Kidney Disease

Area of Science:

• Epigenetics and Molecular Biology
• Nephrology and Urology
• Medicinal Chemistry

Background:

• Epigenetic modifications regulate gene expression and protein function, impacting diseases like cancer and Autosomal Dominant Polycystic Kidney Disease (ADPKD).
• BRD4, an epigenetic regulator, is implicated in ADPKD pathogenesis, suggesting it as a therapeutic target.
• Previous BRD4 inhibitors exhibited off-target kinase activity, necessitating the development of more selective compounds.

Purpose of the Study:

• To design and synthesize novel, selective BRD4 inhibitors to mitigate off-target kinase interactions.
• To evaluate the efficacy of these selective inhibitors in preclinical models of ADPKD.
• To establish targeted BRD4 inhibition as a potential therapeutic strategy for ADPKD.

Main Methods:

• Structure-guided drug design was employed to create selective BRD4 inhibitors.
• Compound 23, a (pyrazol-3-yl) pyrimidin-4-amine derivative, was synthesized and characterized.
• In vitro assays and in vivo studies using cellular and embryonic kidney models of ADPKD, as well as murine models, were conducted to assess efficacy and selectivity.

Main Results:

• Compound 23 demonstrated potent and selective inhibition of BRD4.
• The compound showed significant efficacy in reducing cyst expansion in cellular and embryonic kidney models of ADPKD.
• Positive outcomes were observed in murine models, supporting the in vivo therapeutic potential.

Conclusions:

• Targeted inhibition of BRD4 represents a promising and safe therapeutic strategy for managing ADPKD.
• Compound 23 serves as a lead candidate for further development in ADPKD treatment.
• Selective BRD4 inhibition offers a novel approach to address the neoplastic-like progression characteristic of ADPKD.