Inhibition of apoptosis signal-regulating kinase 1 (ASK1) might be useful in patients with diabetic kidney disease (DKD), according to the results of a new study.

“Previous studies in ASK1 knockout mice demonstrated that ASK1 is a critical mediator of tissue injury and progressive fibrosis, particularly in settings of oxidative stress,” says John Liles, an author on the new paper. “Oxidative stress is a key common driver of tissue injury and fibrosis in diseases such as DKD and nonalcoholic steatohepatitis (NASH), suggesting that ASK1 may be a therapeutic target to halt or reverse fibrosis in these diseases.”

The researchers used high-throughput screening to identify ASK1 inhibitors from a library of approximately 100,000 compounds. Using medicinal chemistry techniques to optimize compounds for potency, selectivity, adsorption, distribution, metabolism and excretion, GS-444217 was established as a potent and highly selective ATP-competitive inhibitor of ASK1.

Liles et al. showed that GS-444217 reduced oxidative-stress-induced ASK1 signalling in rat models of acute kidney injury, preserving renal function by reducing fibrosis, inflammation and tubulointerstitial cell death. They also showed that ASK1 pathway activation was increased in renal biopsies from patients with DKD compared with non-DKD kidneys. A mouse model of DKD showed that GS-444217 attenuated progressive loss of renal function, blocked increases in albuminuria and reduced other pathological features of DKD such as glomerulosclerosis, loss of podocytes and tubulointerstitial fibrosis and apoptosis.

Combining GS-444217 with enalapril, an angiotensin-converting enzyme inhibitor, resulted in greater improvements in glomerulosclerosis and albuminuria than either monotherapy alone in a rodent model of chronic glomerular injury. “Our results show that ASK1 inhibition could be a promising new approach to reduce GFR decline in this high unmet need DKD patient population,” concludes Liles.