Discoidin Domain Receptor (DDR) inhibitors
A Potential Novel Therapeutic Class for Fibrosis
Our research strategy in fibrosis focuses on Discoidin Domain Receptors (DDRs), which drive inflammation and fibrosis in many fibrotic diseases, and inhibition or loss of DDRs reduces this inflammation and fibrosis. This research has resulted in a range of development compounds which are being profiled with the aim to progress through IND enabling work as potential treatments for idiopathic pulmonary fibrosis, liver fibrosis and kidney fibrosis associated with diabetic kidney disease and chronic kidney disease e.g. Alport Syndrome, for which there are currently no specific approved treatments.
Our experienced team of scientists has considerable expertise in understanding the molecular mechanisms underlying fibrosis and novel, druggable therapeutic targets to focus on. We are developing small molecule therapies that aim to halt formation and reverse established fibrosis. By targeting pathways involved in the progression of these devastating diseases, we believe these drugs have potential to be disease-modifying rather than simply providing symptomatic relief.
Overview of DDRs
Discoidin domain receptors (DDRs) were discovered in the 1990s but more recently they have gained new therapeutic targets with potential to treat multiple fibrotic conditions in kidney, lung, and liver disease.1-9
DDRs are receptor tyrosine kinases containing a discoidin homology domain in their extracellular region, which bind to collagen. There are two DDR receptors, DDR1 and DDR2, which act as non-integrin collagen receptors.
On binding of collagen, the DDRs autophosphorylate, initiating various downstream signalling pathways that drive clustering, upregulation and further collagen synthesis. DDR expression is increased in many fibrotic diseases and preclinical proof-of-concept for small molecule inhibitors has been demonstrated in preclinical models of lung and kidney fibrosis. We have developed novel, orally available, selective and potent small molecule DDR inhibitors with drug-like properties.
Currently, there are no selective DDR inhibitors in clinical trials, although several kinase inhibitors developed for other kinases have shown varying degree of DDR specificity. Redx presented a poster on a novel, selective DDR inhibitor, REDX12271, at the American Society of Nephrology (ASN) Kidney Week, November 2022, and we returned to ASN in November 2023 to present REDX13567 preclinical data from a therapeutic Unilateral Ureteral Obstruction (UUO) murine model of kidney fibrosis.
The data presented showed that REDX13567 treatment resulted in:
- A significant reduction in histological markers of both inflammation, kidney injury and fibrosis
- Target engagement in kidney tissue was also demonstrated in phospho-DDR1
(p-DDR1)
The attractive profile of REDX12271 and REDX13567 in preclinical studies have led to the initiation of a wider programme to explore DDR as a potential novel anti-fibrotic target. Redx has developed a portfolio of different DDR inhibitor scaffolds and is currently assessing the optimal candidates to progress.
Chronic Kidney Disease (CKD) and Alport Syndrome
Chronic kidney disease affects 8% to 16% of the population worldwide and is most commonly attributed to diabetes and hypertension. Renal fibrosis, characterised by tubulointerstitial fibrosis and glomerulosclerosis, is one of the final manifestations of CKD as it progresses and is associated with high morbidity.7
Alport Syndrome is an inherited disease that damages the tiny blood vessels in the kidneys and can lead to kidney disease and kidney failure. There is no specific approved treatment for Alport Syndrome, with current standard of care aiming to treat the symptoms and help slow the progression of kidney disease.8 While no reliable prevalence studies are available, Alport Syndrome is estimated to affect less than 200,000 people in the U.S.9, making it a rare disease.
References
- Moll, S, Selective pharmacological inhibition of DDR1 prevents experimentally-induced glomerulonephritis in prevention and therapeutic regime. J Transl Med. 2018 Jun.
- Chiusa, M, Discoidin Domain Receptor 1 Regulates Collagen Transcription by Translocating to the Nucleus. J Am Soc Nephrol. 2019 Sep.
- Kerroch, M, Genetic inhibition of discoidin domain receptor 1 protects mice against crescentic glomerulonephritis. FASEB J. 2012 Oct.
- Dong, W, 2021; Blocking LOXL2 and TGFβ1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis. Thorax. 2021 Jul. IPF Atlas.
- Adams, T, Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci Adv. 2020 Jul.
- Song S, et al. Discoidin domain receptor 1: isoform expression and potential functions in cirrhotic hu1. man liver. Am J Pathol. 2011 Mar;178(3):1134-44.
- Taken in part from Chen TK et al; 2019 Oct 1; 322(13): 1294Ð1304.
- https://www.kidney.org/atoz/content/alport
- https://alportsyndrome.org/about-alport-syndrome/
Our research strategy in fibrosis focuses on Discoidin Domain Receptors (DDRs), which drive inflammation and fibrosis in many fibrotic diseases, and inhibition or loss of DDRs reduces this inflammation and fibrosis. This research has resulted in a range of development compounds which are being profiled with the aim to progress through IND enabling work as potential treatments for idiopathic pulmonary fibrosis, liver fibrosis and kidney fibrosis associated with diabetic kidney disease and chronic kidney disease e.g. Alport Syndrome, for which there are currently no specific approved treatments.
Our experienced team of scientists has considerable expertise in understanding the molecular mechanisms underlying fibrosis and novel, druggable therapeutic targets to focus on. We are developing small molecule therapies that aim to halt formation and reverse established fibrosis. By targeting pathways involved in the progression of these devastating diseases, we believe these drugs have potential to be disease-modifying rather than simply providing symptomatic relief.
Overview of DDRs
Discoidin domain receptors (DDRs) were discovered in the 1990s but more recently they have gained new therapeutic targets with potential to treat multiple fibrotic conditions in kidney, lung, and liver disease.1-9
DDRs are receptor tyrosine kinases containing a discoidin homology domain in their extracellular region, which bind to collagen. There are two DDR receptors, DDR1 and DDR2, which act as non-integrin collagen receptors.
On binding of collagen, the DDRs autophosphorylate, initiating various downstream signalling pathways that drive clustering, upregulation and further collagen synthesis. DDR expression is increased in many fibrotic diseases and preclinical proof-of-concept for small molecule inhibitors has been demonstrated in preclinical models of lung and kidney fibrosis. We have developed novel, orally available, selective and potent small molecule DDR inhibitors with drug-like properties.
Currently, there are no selective DDR inhibitors in clinical trials, although several kinase inhibitors developed for other kinases have shown varying degree of DDR specificity. Redx presented a poster on a novel, selective DDR inhibitor, REDX12271, at the American Society of Nephrology (ASN) Kidney Week, November 2022, and we returned to ASN in November 2023 to present REDX13567 preclinical data from a therapeutic Unilateral Ureteral Obstruction (UUO) murine model of kidney fibrosis.
The data presented showed that REDX13567 treatment resulted in:
- A significant reduction in histological markers of both inflammation, kidney injury and fibrosis
- Target engagement in kidney tissue was also demonstrated in phospho-DDR1
(p-DDR1)
The attractive profile of REDX12271 and REDX13567 in preclinical studies have led to the initiation of a wider programme to explore DDR as a potential novel anti-fibrotic target. Redx has developed a portfolio of different DDR inhibitor scaffolds and is currently assessing the optimal candidates to progress.
Chronic Kidney Disease (CKD) and Alport Syndrome
Chronic kidney disease affects 8% to 16% of the population worldwide and is most commonly attributed to diabetes and hypertension. Renal fibrosis, characterised by tubulointerstitial fibrosis and glomerulosclerosis, is one of the final manifestations of CKD as it progresses and is associated with high morbidity.7
Alport Syndrome is an inherited disease that damages the tiny blood vessels in the kidneys and can lead to kidney disease and kidney failure. There is no specific approved treatment for Alport Syndrome, with current standard of care aiming to treat the symptoms and help slow the progression of kidney disease.8 While no reliable prevalence studies are available, Alport Syndrome is estimated to affect less than 200,000 people in the U.S.9, making it a rare disease.
References
- Moll, S, Selective pharmacological inhibition of DDR1 prevents experimentally-induced glomerulonephritis in prevention and therapeutic regime. J Transl Med. 2018 Jun.
- Chiusa, M, Discoidin Domain Receptor 1 Regulates Collagen Transcription by Translocating to the Nucleus. J Am Soc Nephrol. 2019 Sep.
- Kerroch, M, Genetic inhibition of discoidin domain receptor 1 protects mice against crescentic glomerulonephritis. FASEB J. 2012 Oct.
- Dong, W, 2021; Blocking LOXL2 and TGFβ1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis. Thorax. 2021 Jul. IPF Atlas.
- Adams, T, Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci Adv. 2020 Jul.
- Song S, et al. Discoidin domain receptor 1: isoform expression and potential functions in cirrhotic hu1. man liver. Am J Pathol. 2011 Mar;178(3):1134-44.
- Taken in part from Chen TK et al; 2019 Oct 1; 322(13): 1294Ð1304.
- https://www.kidney.org/atoz/content/alport
- https://alportsyndrome.org/about-alport-syndrome/
