Discovery of Novel, Potent inhibitors of Hydroxy Acid Oxidase 1 Using DNA-Encoded Chemical Library Screening

Primary hyperoxaluria type 1 (PH1) is an inherited rare liver disorder of glyoxylate metabolism, which is caused by mutations in the enzyme alanine-glyoxylate aminotransferase (AGXT). AGXT converts glyoxylate, the product of hydroxy acid oxidase 1 (HAO1), to glycine in the liver. The reduced activity of AGXT in PH1 patients results in increased levels of oxalate, which can lead to progressive kidney deterioration. Inhibition of HAO1 is a strategy used to mitigate the accumulation of toxic oxalate. Utilizing DNA-encoded discovery platform, we were able to identify several novel chemical series of potent HAO1 binders. Horseradish peroxidase (HRP) coupled biochemical assay and CHO-GO cell rescue assay were used to determine IC50 values and cell rescue potencies of compounds, respectively. Compounds with improved potency and absorption, distribution, metabolism, and excretion (ADME) / pharmacokinetic (PK) properties were developed.