Targeting of a Bile Acid Receptor, Takeda G Protein Receptor 5 [TGR5], by a Novel First-in-Class Competitive Antagonist, SBI-364, Diminishes Hepatic and Renal Cystogenesis in Polycystic Liver and Kidney Disease

Polycystic kidney disease (PKD) and associated polycystic liver disease (PLD) are genetic disorders with limited therapeutic options. In this work, we report SBI-364, a novel first in-class competitive antagonist of a G protein-coupled bile acid receptor, Takeda G protein receptor 5 (TGR5), as a potent small-molecule compound for concurrent treatment of both PLD and PKD. We found that elevated expression of TGR5 in hepatic epithelial cells (cholangiocytes) and renal epithelial cells (REC) from which cysts originate contributes to disease progression. To pharmacologically reduce TGR5-mediated cystogenesis, we developed a competitive TGR5 antagonist, SBI-364, and demonstrated in <i>in vitro</i> and <i>in vivo</i> models of PKD and PLD that SBI-364 effectively inhibits the proliferation of human and PCK rat (an animal model of PLD and PKD) cystic cholangiocytes and REC in a time- and dose-dependent manner, decreases the growth of cystoids formed in a 3-D culture by cholangiocytes and REC isolated from PCK rats, and diminishes renal and hepatic cystogenesis in PCK rats by decreasing the cAMP-mediated proliferation of cystic cholangiocytes and REC in a dose- and sex-dependent manner. Mechanistically, SBI-364 reduces the coupling of TGR5 with G_αs proteins in both cystic cholangiocytes and REC, inhibiting cAMP-mediated pathways and cystogenic processes. Thus, our study demonstrates that SBI-364 decreases the progression of hepatic and renal cystogenesis by targeting TGR5 in liver and kidney and could be considered as a novel therapeutic option for simultaneous treatment of PLD and PKD.