@misc{10481/111200,
year = {2026},
month = {1},
url = {https://hdl.handle.net/10481/111200},
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.},
organization = {Group BIO-250},
organization = {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.)},
organization = {National Science Foundation grant 2537597 (A.Y.J., N.D., A.W.O., and O.R.)},
organization = {LSUHS Center for Cardiovascular Diseases and Sciences Malcolm Feist Postdoctoral Fellowship (S.R.)},
organization = {NIH Predoctoral T32 Fellowship HL155022 (K.S.E.R.)},
organization = {American Heart Association Postdoctoral Fellowships 24POST1196650 (S.D.), 24POST1199805 (S.K.A.) and 25POST1352845 (D.K.)},
organization = {Project 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.)},
organization = {Universidad de Granada / CBUA},
publisher = {American Chemical Society},
keywords = {Primary Hyperoxaluria},
keywords = {Dual Inhibitors},
keywords = {Glycolate Oxidase},
keywords = {Lactate Dehydrogenase},
keywords = {Hydrophobic Tag},
keywords = {Targeted Protein Degradation},
keywords = {Oxalate Reduction},
keywords = {Oxalate},
keywords = {small molecule},
title = {Targeting Oxalate Production by Combining Enzyme Inhibition and Proteolysis Activation: A Novel Therapeutic Approach for Primary Hyperoxaluria Type 1},
doi = {10.1021/acs.jmedchem.5c02055},
author = {Arias Bordajandi, Fabio and Sixto-López, Yudibeth and Richard, Koral S. E. and Das, Sandeep and Anand, Sumit K. and Luque Navarro, Pilar María and Bañuelos Sánchez, Guillermo and Pacheco García, Juan Luis and Gade, Reethika and McKinney, M. Peyton and Kumar, Dhananjay and Maxie, Jemiah and Corr, W. Rylan and Pandey, Nilesh and Kaur, Harpreet and Ding, Jibin and Tan, Lin and Scott, Elisha and Nam, Hyung and Gottlieb, Eyal and Orr, A. Wayne and Dhanesha, Nirav and Yurdagul, Arif and Pey Rodríguez, Ángel Luis and Franco Montalbán, Francisco and Gómez Vidal, José Antonio and Rom, Oren and Díaz Gavilán, Mónica},
}