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.