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

Epigenetic
modulation plays a pivotal role in restraining tumor
progression by governing gene expression and protein function. Autosomal
dominant polycystic kidney disease (ADPKD), characterized by neoplastic-like
progression, can be managed by inhibiting cyst expansion. Of note,
the epigenetic regulator BRD4 has been implicated in ADPKD’s
development. Our prior research unveiled a class of (pyrazol-3-yl)
pyrimidin-4-amine compounds as potent BRD4 inhibitors with additional
kinase inhibition, which might induce unwanted biological activities.
To address this, this study focused on creating selective BRD4 inhibitors
through structure-guided design, minimizing off-target kinase interactions.
Specifically, compound 23 emerged as an efficacious and
selective BRD4 inhibitor in cellular and embryonic kidney models of
ADPKD, along with encouraging outcomes in murine models. Collectively,
these results highlight the therapeutic potential of targeted BRD4
inhibition as a safe and efficacious strategy for managing ADPKD.