GV-001, An Oral Available Histone Deacetylase 6 Inhibitor for the Treatment of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a rare genetic disorder characterized by progressive cyst formation. Emerging evidence suggests that histone deacetylase 6 (HDAC6) plays a pivotal role in the regulation of disease progression. In this study, a series of quinazoli-4-one derivatives were designed and synthesized, among which compound 6a (GV-001) exhibited superior potency and selectivity in both enzyme inhibition (IC50 = 1.18 nM) and immunoblotting assays. Subsequent analysis using the BioMAP fibrosis panel and an in vitro human kidney cyst model revealed that GV-001 mitigates inflammatory and fibrotic markers, such as sIL-6 and Collagen I, while effectively suppressing cyst growth. Additionally, GV-001 displayed favorable oral bioavailability (36%) and kidney exposure (AUC(0-t): 1790 ng·h/mL) in rats, whereas oral administration produced significant therapeutic efficacy in an ADPKD mouse model, along with upregulation of PC1 expression. These results support GV-001 as a promising and selective HDAC6 inhibitor for the treatment of ADPKD.