ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: SA-OR90

Development of Novel Selective DDR1 Inhibitors with the Potential to Treat CKD

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Guisot, Nicolas E.S., Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Wilcock, Daniel J., Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Bhamra, Inder, Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Eckersley, Kay, Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Douglas, Gayle E., Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Ho, Kelvin, Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Jones, Cliff, Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Leng, Daniel J., Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Lloyd-Weston, Jack W., Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Marshall, Amy B., Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Mckeever, Helen, Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Phillips, Caroline, Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Preece, Shân, Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Ryan, James, Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Street, Robert J., Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
  • Armer, Richard, Redx Pharma plc, Macclesfield, Cheshire, United Kingdom
Background

Discoidin domain receptors (DDRs) are collagen-activated receptor tyrosine kinases which have been shown to have increased expression in many fibrotic diseases. Inhibition or knockout of DDR1 has previously been shown to decrease fibrosis and protect kidney function in multiple preclinical mouse models of kidney fibrosis. However, to date there are no approved selective inhibitors of DDR1 in the clinic. In this study, the protective role of REDX-DDR1, a novel and selective orally bioavailable small molecule inhibitor of DDR1 was investigated in a mouse unilateral ureteral obstruction (UUO) model.

Methods

For therapeutic intervention, mice were subjected to UUO and subsequently from day 5 to treatment with vehicle, REDX-DDR1 via oral gavage. 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

REDX-DDR1 exhibits nanomolar potency in cells and target engagement in the kidney as measured by suppression of phospho-DDR1. REDX-DDR1 is highly selective when tested against a panel of 468 kinases. REDX-DDR1 has a favourable in vitro and in vivo ADME profile including good in vivo exposure across species and low potential for drug-drug interactions. Early safety pharmacology assessment showed no findings in standard ion channel panels. In vitro genetic toxicology showed no genotoxic findings in 5-strain Ames test. The favourable selectivity and pharmacokinetic profiles of REDX-DDR1 allow for selective inhibition of DDR1 in mouse models of chronic kidney disease.
Animals treated with REDX-DDR1 had a significant reduction in histological markers of inflammation and fibrosis in the therapeutic mouse UUO model. REDX-DDR1 suppressed inflammation and fibrosis as measured by F4/80, α-SMA and PSR respectively. In addition REDX-DDR1 suppressed a number of pro-fibrotic genes.

Conclusion

These data show that selective inhibition of the DDR1 receptor via REDX-DDR1 results in anti-fibrotic efficacy in the UUO model. Selective inhibition of DDR1 represents an attractive approach for further investigation towards the development of new treatments for CKD.

Funding

  • Commercial Support – Redx Pharma Plc