2. Academic Validation
  3. Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria

Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria

  • ACS Med Chem Lett. 2021 May 20;12(7):1116-1123. doi: 10.1021/acsmedchemlett.1c00196.
Jinyue Ding 1,  Rajesh Gumpena 2,  Marc-Olivier Boily 1,  Alexandre Caron 1,  Oliver Chong 1,  Jennifer H Cox 1,  Valerie Dumais 1,  Samuel Gaudreault 1,  Aaron H Graff 2,  Andrew King 1,  John Knight 3,  Renata Oballa 1,  Jayakumar Surendradoss 1,  Tim Tang 1,  Joyce Wu 1,  W Todd Lowther 2,  David A Powell 1
Affiliations

Affiliations

  • 1 Chinook Therapeutics, 210-887 Great Northern Way, Vancouver, British Columbia, V5T 4T5, Canada and 1600 Fairview Avenue E, Suite #100, Seattle, Washington 98102, United States.
  • 2 Center for Structural Biology, Department of Biochemistry, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, United States.
  • 3 Department of Urology, University of Alabama at Birmingham, 720 20th Street South, Birmingham, Alabama 35294, United States.
PMID: 34267881 DOI: 10.1021/acsmedchemlett.1c00196
Abstract

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 structure-based 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.

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