Chronic kidney disease (CKD) is a major public health crisis: +15M people in the US, including 38% of anyone over 65, will develop this disease. CKD is the progressive worsening of kidney function, culminating ultimately in dialysis and renal failure. Causes of CKD have mostly been attributed to upstream indications such as Hypertension, Type-II diabetes and dyslipidemia and thus standard pharmacological interventions like beta blockers, Metformin or statins are prescribed often with limited efficacy.
Recent evidence has emerged that ferroptosis, a new form of regulated cell death resulting from an accumulation of toxic free radicals on specific poly-unsatured fatty acids, plays a central role in kidney damage associated with Type II diabetes. Ferroptosis-prevention proteins like GPX4 and system-Xc are dramatically reduced in kidney biopsies of diabetic patients (Figure 1). Scientists have observed abnormally high levels of Ferritin (a strong biomarker of free-Iron) in serum of diabetic patients. And recent molecular work suggests that high levels of glucose, on its own, is sufficient to induce lipid peroxidation and renal cell death via ferroptosis (Figure 2).
Over the last decade, scientists across the world have made major advances in our understanding of ferroptosis and the specific proteins we might inhibit or activate to prevent this pathological pathway in CKD. Inhibition of ACSL4 is an exciting approach to ferroptosis-prevention given ACSL4’s role in preventing the accumulation of specific phospholipids known to be susceptible to peroxidation.
At Arpeggio, we utilized our GRETATM screening technology to identify compounds that block the Ferroptosis pathway (Figure 3). Computational modeling of these compounds indicate completely novel ACSL4 binders. Following hit-to-lead optimization, we assessed our most drug-like small molecule in an in vivo mouse model of kidney injury and noted prevention of increased blood urea and creatinine levels upon treatment of our compound. Taken together, Arpeggio is rapidly advancing a novel treatment of CKD by blocking ferroptosis. Given the strong role ferroptosis plays in CKD progression, we believe our therapy may dramatically improve the lives of millions of patients across the world.
