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.

表观遗传调控（Epigenetic modulation）通过调控基因表达与蛋白质功能，在抑制肿瘤进展中发挥关键作用。常染色体显性遗传性多囊肾病（Autosomal dominant polycystic kidney disease, ADPKD）以类肿瘤样进展为特征，可通过抑制囊肿扩张进行干预。值得注意的是，表观遗传调控因子BRD4已被证实与ADPKD的发生发展相关。我们此前的研究揭示了一类(吡唑-3-基)嘧啶-4-胺类化合物，其可作为强效BRD4抑制剂，同时兼具激酶抑制活性，这可能引发非靶标生物学效应。为此，本研究通过结构导向设计开发选择性BRD4抑制剂，以最大限度减少激酶脱靶相互作用。具体而言，化合物23在ADPKD的细胞模型与胚胎肾模型中展现出高效且高选择性的BRD4抑制活性，同时在小鼠模型中取得了令人鼓舞的实验结果。综上，本研究结果证实了靶向BRD4抑制作为一种安全有效的ADPKD干预策略的治疗潜力。