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

  • J Med Chem. 2026 Jan 2:10.1021/acs.jmedchem.5c02055. doi: 10.1021/acs.jmedchem.5c02055.
Fabio Arias  1  2  3 ,  Sumati Rohilla  3 ,  Yudibeth Sixto-López  1  2 ,  Koral S E Richard  3 ,  Sandeep Das  3 ,  Sumit K Anand  3 ,  Pilar Maria Luque-Navarro  1  2 ,  Guillermo Bañuelos-Sanchez  1 ,  Juan Luis Pacheco-García  4 ,  Reethika Gade  3 ,  M Peyton McKinney  3 ,  Dhananjay Kumar  5 ,  Jemiah Maxie  3 ,  W Rylan Corr  3 ,  Nilesh Pandey  3 ,  Harpreet Kaur  3 ,  Jibin Ding  6 ,  Lin Tan  6 ,  Elisha Scott  3 ,  Hyung Nam  3 ,  Eyal Gottlieb  6 ,  A Wayne Orr  3  5 ,  Nirav Dhanesha  3 ,  Arif Yurdagul Jr  3  5 ,  Angel L Pey  2  4 ,  Francisco Franco-Montalbán  1  2 ,  José A Gómez Vidal  1  2 ,  Oren Rom  3  5 ,  Mónica Díaz-Gavilán  1  2
Affiliations
  • 1. Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Campus Cartuja s/n, 18071 Granada, Spain.
  • 2. Unidad de Excelencia en Química Aplicada a Biomedicina y Medioambiente, Universidad de Granada, Av. Fuentenueva s/n, 18071 Granada, Spain.
  • 3. Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana 71103, United States.
  • 4. Departamento de Química Física e Instituto de Biotecnología, Universidad de Granada, Av. Fuentenueva s/n, 18071 Granada, Spain.
  • 5. Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana 71103, United States.
  • 6. Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
PMID: 41480893 DOI: 10.1021/acs.jmedchem.5c02055
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 (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.

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