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Abstract: TH-PO877

ROCK2 Inhibitors for the Treatment of CKD

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Offer, Emily P., Redx Pharma Plc, Macclesfield, United Kingdom
  • Guisot, Nicolas Emmanuel Stephane, Redx Pharma Plc, Macclesfield, United Kingdom
  • Best, Stuart A., Redx Pharma Plc, Macclesfield, United Kingdom
  • Pesnot, Thomas, Concept life sciences, Macclesfield, United Kingdom
  • MacFaul, Philip, Redx Pharma Plc, Macclesfield, United Kingdom
  • Ceccarelli, Sara, Redx Pharma Plc, Macclesfield, United Kingdom
  • Eckersley, Kay, Redx Pharma Plc, Macclesfield, United Kingdom
  • Pitt, Gary R. w., Walter and Eliza Hall Institute, Melbourne, New South Wales, Australia
  • Bunyard, Peter R., Redx Pharma Plc, Macclesfield, United Kingdom
  • Jones, Clifford D., Redx Pharma Plc, Macclesfield, United Kingdom
  • Armer, Richard, Redx Pharma Plc, Macclesfield, United Kingdom
Background


The Rho Associated Coiled-Coil Containing Protein Kinase (ROCK) serine/threonine kinases, ROCK1 and ROCK2, are central signalling proteins that regulate a range of cellular responses such as cell migration, contraction, proliferation, cytokine and growth factor expression, and integrin-mediated cell-to-cell adhesions. These processes are central to the aberrant wound healing response that can progress to chronic injury and organ fibrosis. Small molecule pan-ROCK inhibitors have been shown to be anti-fibrotic in a range of animal models including: bleomycin induced lung fibrosis, high fat diet induced liver fibrosis and models of kidney fibrosis. However, ROCK signalling is also involved in regulating vascular tone and pan-ROCK inhibitors have been shown to cause hyperaemia and hypotension, limiting their use in patients. There is significant homology between the ROCK1 and ROCK2 isoforms however there is evidence that ROCK2 has additional roles distinct from ROCK1 in both inflammation and wound healing. For example, ROCK2 is upregulated in diabetic kidney disease and in the diseased vascular network of patients at risk of chronic kidney disease (CKD).

Methods

Redx have developed a series of potent ROCK2 inhibitors, that are highly selective against ROCK1 and a panel of 468 kinases.

Results

Redx ROCK2 selective compounds potently suppress the release of pro-fibrotic factors from kidney mesangial cells, cultured in high glucose. In a model of acute kidney injury, our selective ROCK2 tool compound reduced podocyte damage, and the expression of inflammatory and profibrotic genes in the kidney.

In addition, in a telemetered rat study, no significant reduction in blood pressure or increase in heart rate was recorded, indicating that a selective ROCK2 inhibitor could avoid these side-effects typically observed with pan-ROCK inhibitors and increase the safety window at efficacious doses.

Conclusion


Highly selective ROCK2 inhibitors, therefore, could provide a novel and effective therapy for patients with progressive kidney fibrosis who currently have few and largely ineffective therapy options.

Funding

  • Commercial Support