Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria

Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structurebased drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC50 of 88 nM for oxalate reduction in an Agxt-knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.

Automated summary

This study investigated the potential advantage of dual inhibition of glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) in treating primary hyperoxaluria (PH), developing a series of novel dual GO/LDHA inhibitors. However, limited by poor liver exposure, these dual inhibitors failed to show significant PD modulation in an in vivo mouse model, highlighting challenges in optimizing liver exposures for diacid containing compounds and the limited benefit of dual GO/LDHA inhibitors over single agents in an in vitro setting.