Targeting Oxalate Production by Combining Enzyme Inhibition and Proteolysis Activation: A Novel Therapeutic Approach for Primary Hyperoxaluria Type 1

Primary hyperoxaluria
type 1 (PH1) is a rare genetic
disorder caused
by hepatic oxalate overproduction due to alanine-glyoxylate aminotransferase
(AGXT) deficiency. Therapeutic strategies targeting glycolate oxidase
(GO) and lactate dehydrogenase A (LDHA), key enzymes in glyoxylate
metabolism, have shown promise in reducing oxalate burden. However,
recently approved siRNA therapies remain limited by high cost, unfavorable
pharmacokinetics, and limited global accessibility. We report the
development of compound 2, a dual GO/LDHA inhibitor (Ki = 390 and 40 nM, respectively) that also promotes
hydrophobic tag-mediated autophagic degradation of LDHA. Its efficacy
was evaluated in Agxt–/– mice, both in primary hepatocytes and through oral administration.
Treatment significantly reduced hepatic LDHA levels, urinary oxalate
excretion, and renal calcium-oxalate crystal deposition. These findings
support compound 2 as a first-in-class, orally bioavailable
small molecule with dual inhibitory and proteolytic activity, offering
a novel therapeutic candidate for PH1 and other oxalate-related pathologies.