Discoidin Domain Receptor (DDR) inhibitors

Discoidin domain receptors (DDRs) were discovered in the 1990s but more recently they have gained traction as new therapeutic targets with potential to treat multiple fibrotic conditions. 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 selective and potent small molecule DDR inhibitors with drug-like characteristics that are now in lead optimisation phase.

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. We presented a poster on a novel, selective DDR1 inhibitor at the American Society of Nephrology Kidney Week, November 2022.