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Abstract: SA-PO244

Developing a Small Molecule Therapeutic to Treat Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Al-Ali, Hassan, University of Miami School of Medicine, Miami, Florida, United States
  • Varona Santos, Javier T., University of Miami School of Medicine, Miami, Florida, United States
  • Donow, Haley M., Florida International University, Miami, Florida, United States
  • Giulianotti, Marc, Florida International University, Miami, Florida, United States
  • Molina David, Judith T., University of Miami School of Medicine, Miami, Florida, United States
  • Fornoni, Alessia, University of Miami School of Medicine, Miami, Florida, United States
  • Merscher, Sandra M., University of Miami School of Medicine, Miami, Florida, United States

Group or Team Name

  • Katz Center Drug Discovery
Background

Injury and loss of podocytes underly the development and progression of DKD. We previously showed that accumulation of lipid droplets (LDs) in podocytes is associated with increased lipotoxicity and cell death, and that reducing LD accumulation in podocytes combats DKD. We hypothesize that a targeted small molecule that directly blocks LD accumulation in podocytes can halt or reverse the progression of DKD.

Methods

A robust phenotypic screening assay utilizing immortalized human podocytes was developed to identify compounds that reduce LD accumulation in these cells. A combinatorial chemical library from the Torrey Pines Institute for Molecular Studies (TPIMS) containing over 45 million molecules was screened in the assay. Hits were identified based on their ability to reduce LD accumulation and rescue podocytes from cell death. RNAseq libraries from podocytes treated with one of the identified hits in the presence of sera from subjects with or without DKD were generated and analyzed.

Results

The assay identified several hits from the FIU library. Preliminary structure activity relationship (SAR) studies showed strong feasibility for hit-to-lead optimization of one series. A representative compound reduced the expression of genes related to TNF-signaling, a pathway associated with LD accumulation and podocyte injury, and the expression of lysosome-associated membrane glycoprotein (LAMP), which correlates with improved autophagy/lipophagy. Follow up mechanistic studies confirmed that the compound induces autophagic flux in podocytes, including strong induction of lipophagy, providing a candidate mechanism by which the compound protects these cells from lipotoxic stress. Our initial medicinal chemistry efforts have generated lead-like analogs that are appropriate for in vivo testing.

Conclusion

Our screen identified a promising molecular series that strongly reverses features of podocyte toxicity and death in DKD. We have launched a medicinal chemistry campaign to extend the SAR studies and have generated optimized compounds for in vivo validation in a mouse model of DKD. The compounds are currently being tested in db/db mice. Our results will enable the identification of novel drug targets and initiate the development of a therapeutic candidate for DKD.

Funding

  • NIDDK Support