Newly Identified DDR1 I Inhibitor Can Prevent Kidney Fibrosis, Loss of Function in Alport Syndrome Mice

Inhibition of the DDR1 enzyme with a newly identified small molecule compound can prevent renal tissue scarring and renal function loss in a mouse model of Alport syndrome, a study shows.

The study, “DNA-encoded library-derived DDR1 inhibitor prevents fibrosis and renal function loss in a genetic mouse model of Alport syndrome,” was published in the journal ACS Chemical Biology.

Activation of DDR1 enzyme is known to contribute to the deposition and accumulation of collagen (a key step in fibrosis development) in the kidney. Genetic variants of the DDR1 gene have been linked to susceptibility and disease progression of childhood renal damage, further strengthening the role of DDR1 in human renal diseases.

Although DDR1 may represent an attractive target for the treatment of kidney diseases, efforts to identify an appropriate compound to modulate its activity have been unsuccessful. This is mainly due to the lack of specificity of the investigated molecules.

Now, a team led by researchers at Roche investigated possible small molecule inhibitors that not only could block DDR1 activity but also that of DDR2, another similar enzyme involved in renal fibrosis.

After a detailed structural and chemical screen, the team identified a compound — referred to as compound 2.45 — that could inhibit DDR1 activity by 70%, and DDR2 activity 14-fold compared to all other enzymes, “demonstrating the outstanding selectivity of the compound,” the researchers said.

Using an experimental renal cell model, the team found that compound 2.45 could prevent the production of collagen and other molecules involved in renal tissue remodeling.

Next, they treated mice with autosomal recessive Alport syndrome, lacking the Col4a3 gene, with the new DDR1 inhibitor. The treatment reduced DDR1 activation in the animals, which was associated with a significant reduction in albumin/creatinine ratio and blood urea nitrogen — two hallmarks of kidney damage and loss of function.

In addition, treatment with the DDR1 inhibitor 2.45 resulted in a significant reduction of kidney fibrosis (scarring) and collagen accumulation.

These results demonstrate for the first time that DDR1 inhibition with a small molecule can prevent collagen-stimulated tissue remodeling, reduce renal fibrosis, and preserve renal function in a mouse model of Alport syndrome, indicating “the real therapeutic value of selectively inhibiting DDR1,” the team stated.

As Alport syndrome shares several features with chronic kidney disease (CKD), the team believes that “selective pharmacological inhibition of DDR1 might be an interventional strategy also in the context of CKD,” they wrote. CKD affects 10% of the global population.