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

Authors

Fabio Arias
Sumati Rohilla
Yudibeth Sixto-López
Koral S E Richard
Sandeep Das
Sumit K Anand
Pilar Maria Luque-Navarro
Guillermo Bañuelos-Sanchez
Juan Luis Pacheco-García
Reethika Gade
M Peyton McKinney
Dhananjay Kumar
Jemiah Maxie
W Rylan Corr
Nilesh Pandey
Harpreet Kaur
Jibin Ding
Lin Tan
Elisha Scott
Hyung Nam
Eyal Gottlieb
A Wayne Orr
Nirav Dhanesha
Arif Yurdagul
Angel L Pey
Francisco Franco-Montalbán
José A Gómez Vidal
Oren Rom
Mónica Díaz-Gavilán

Language

English

Publication Date

2-12-2026

Journal

Journal of Medicinal Chemistry

DOI

10.1021/acs.jmedchem.5c02055

PMID

41480893

PMCID

PMC12795515

PubMedCentral® Posted Date

1-2-2026

PubMedCentral® Full Text Version

Post-print

Abstract

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 (K i = 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.

Keywords

Hyperoxaluria, Primary, Animals, Oxalates, Mice, Proteolysis, Alcohol Oxidoreductases, Enzyme Inhibitors, Transaminases, L-Lactate Dehydrogenase, Humans, Mice, Knockout, Hepatocytes, Male, Mice, Inbred C57BL

Published Open-Access

yes

Recommended Citation

Arias, Fabio; Rohilla, Sumati; Sixto-López, Yudibeth; et al., "Targeting Oxalate Production by Combining Enzyme Inhibition and Proteolysis Activation: A Novel Therapeutic Approach for Primary Hyperoxaluria Type 1" (2026). Faculty, Staff and Student Publications. 5758.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5758