A Therapeutic Lead Compound for Diabetic Kidney Disease with a Unique Lipophagy Activation Mechanism

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Background: In 2021, 537 million people worldwide had diabetes, and this number is expected to increase to 783 million by 2045. Approximately 30% of individuals with diabetes develop Diabetic kidney disease (DKD), which ultimately leads to end stage renal failure. We previously demonstrated that lipid droplets (LDs) accumulation in podocytes leads to increased lipotoxicity and cell death in DKD. Furthermore, we reported that reducing LD accumulation in podocytes preserves cell function and attenuates albuminuria in experimental DKD. Drugs that reduce lipids systemically do not prevent DKD progression. We hypothesize that specifically reducing LD accumulation in podocytes prevents DKD progression. Methods: We developed a phenotypic assay using immortalized human podocytes and deployed it to screen a combinatorial library. We identified a novel series of hit compounds, from which we generated a lead candidate with improved drug-like properties. We performed RNAseq, molecular biology and phenotypic profiling (Cell Painting) analyses to elucidate the mechanism of action (MoA) of these compounds. Finally, we tested the lead compound in a murine model of DKD. Results: Our screen identified a series of novel compounds that effectively reduced LD accumulation in stressed podocytes. Mechanistic studies revealed that the lead candidate, compound 2726.007, activates autophagy/lipophagy, thereby reducing LD accumulation in stressed podocytes and rescuing them from cell death. When compared to other autophagy inducers with diverse MoAs, including metformin, rapamycin, and L690,330, only compound 2726.007 decreased LD accumulation in stressed podocytes and prevented cell death. Unbiased phenotypic-based profiling of these compounds further demonstrated that compound 2726.007 has a unique MoA that is not reproduced by the other autophagy inducers. Importantly, compound 2726.007 significantly reduced albuminuria and renal damage in db/db mice. Conclusion: Taken together, we have developed a therapeutic lead compound that reduces LD accumulation in podocytes by activating lipophagy through a mechanism distinct from other autophagy inducers, thereby preventing DKD progression. Next steps include lead optimization and preclinical development to ultimately advance the candidate towards clinical trials. Funding: NIDDK Support, Private Foundation Support

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