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Abstract: TH-PO433

REDX12271 Is a Novel, Selective DDR1 Inhibitor With the Potential to Treat Multiple Chronic Kidney Diseases

Session Information

Category: Glomerular Diseases

  • 1301 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Eckersley, Kay, Redx Pharma plc, Nether Alderley, United Kingdom
  • Bhamra, Inder, Redx Pharma plc, Nether Alderley, United Kingdom
  • Ryan, James, Redx Pharma plc, Nether Alderley, United Kingdom
  • Andrae, Michal S., Redx Pharma plc, Nether Alderley, United Kingdom
  • Wilcock, Daniel J., Redx Pharma plc, Nether Alderley, United Kingdom
  • Preece, Shân, Redx Pharma plc, Nether Alderley, United Kingdom
  • Bunyard, Peter R., Redx Pharma plc, Nether Alderley, United Kingdom
  • Jones, Clifford D., Redx Pharma plc, Nether Alderley, United Kingdom
  • Armer, Richard, Redx Pharma plc, Nether Alderley, United Kingdom
Background

Discoidin domain receptors (DDRs) are collagen-activated receptor tyrosine kinases which have been shown to be highly expressed in many fibrotic diseases. The protective role of REDX12271, a novel and selective orally bioavailable small molecule inhibitor of DDR1, was investigated in a mouse unilateral ureteral obstruction (UUO) model. REDX12271 exhibits nanomolar potency in cells and target engagement in the kidney as measured by suppression of phospho-DDR1. Efficacy was demonstrated via suppression of pro-fibrotic genes and through reduction of α-SMA and collagen deposition.

Methods

For the prophylactic regime, mice were subjected to treatment with vehicle or REDX12271 via oral gavage at 15 mg/kg BID and 50 mg/kg BID for one day prior to surgery and for a further 7 days post UUO. Control animals were not subjected to UUO. At sacrifice, obstructed kidneys were collected and processed for kidney markers of inflammation and fibrosis.
For therapeutic intervention, mice were subjected to UUO and subsequently from day 5 to treatment with vehicle or REDX12271 via oral gavage at 15 mg/kg BID and 50 mg/kg BID. Animals were sacrificed at day 10 and kidneys were collected and processed for histological analysis of collagen deposition and myofibroblast transformation in stained tissue sections.

Results

Animals treated with REDX12271 had a statistically significant reduction in histological markers of inflammation and fibrosis in the mouse UUO model. REDX12271 suppressed inflammation and fibrosis in the prophylactic model of UUO as measured by histological staining for F4/80 and α-SMA respectively. In the therapeutic regime, animals treated with REDX12271 had a statistically significant reduction in fibrosis compared to vehicle as measured by histological staining for α-SMA and Picrosirius Red.

Conclusion

These data show that REDX12271 reduces inflammation and fibrosis in UUO models. To our knowledge this is the first example of selective inhibition of DDR1 with a small molecule giving rise to efficacy in mouse UUO models. Selective inhibition of DDR1 represents an attractive approach for further investigation towards the development of new treatments for CKD.

Funding

  • Commercial Support