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 <b>23</b> 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.