Targeting Oxalate Production by Combining Enzyme Inhibition and Proteolysis Activation: A Novel Therapeutic Approach for Primary Hyperoxaluria Type 1 Arias Bordajandi, Fabio Sixto-López, Yudibeth Richard, Koral S. E. Das, Sandeep Anand, Sumit K. Luque Navarro, Pilar María Bañuelos Sánchez, Guillermo Pacheco García, Juan Luis Gade, Reethika McKinney, M. Peyton Kumar, Dhananjay Maxie, Jemiah Corr, W. Rylan Pandey, Nilesh Kaur, Harpreet Ding, Jibin Tan, Lin Scott, Elisha Nam, Hyung Gottlieb, Eyal Orr, A. Wayne Dhanesha, Nirav Yurdagul, Arif Pey Rodríguez, Ángel Luis Franco Montalbán, Francisco Gómez Vidal, José Antonio Rom, Oren Díaz Gavilán, Mónica Primary Hyperoxaluria Dual Inhibitors Glycolate Oxidase Lactate Dehydrogenase Hydrophobic Tag Targeted Protein Degradation Oxalate Reduction Oxalate small molecule This study was partially supported by grant PID2022–141783OB-C21 funded by MICIU/AEI/10.13039/501100011033 and by “ERDF/EU” (M.D.G; with salary/contract support for Y.S.L. and P.L.N.); National Institutes of Health (NIH) grants DK136685 (O.R.), DK134011 (O.R.) HL150233 (O.R.), HL180481 (A.Y.J.), HL167758 (A.Y.J.), HL145131 (A.Y.J.); National Science Foundation grant 2537597 (A.Y.J., N.D., A.W.O., and O.R.); the LSUHS Center for Cardiovascular Diseases and Sciences Malcolm Feist Postdoctoral Fellowship (S.R.); NIH Predoctoral T32 Fellowship HL155022 (K.S.E.R.); and the American Heart Association Postdoctoral Fellowships 24POST1196650 (S.D.), 24POST1199805 (S.K.A.) and 25POST1352845 (D.K.). Universidad de Granada / CBUA. 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. 2026-02-18T12:28:51Z 2026-02-18T12:28:51Z 2026-01-02 journal article Arias Bordajandi, Fabio et al. 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;69(3):2258–2286. DOI:10.1021/acs.jmedchem.5c02055 https://hdl.handle.net/10481/111200 10.1021/acs.jmedchem.5c02055 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License American Chemical Society