March 2024

Arpeggio Pipeline: Chronic Kidney Disease

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).

Figure 1. Adapted from Kim et al 2021, kidney biopsies taken from diabetic patients have significantly lower levels of SLC7A11 and GPX4, known proteins that protect cells from toxic lipid peroxides and ultimately ferroptosis.  

Figure 2. Adapted from Wu et al 2021, high glucose (HG) levels in cell culture serum is sufficient to reduce the expression of anti-Ferroptosis proteins like GPX4 and up-regulate mRNA markers of Ferroptosis such as ACSL4, PTGS2, and NOX1.

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.

Figure 3. Arpeggio’s screening strategy to find selective blockers of the ferroptosis pathway. Left: each dot represents a compound from a highly curated small molecule library ranked to the extent that it can prevent ferroptosis. Right: a ferroptosis prevention score is calculated by the amount of blockage in a dose-dependent increase in the ferroptosis pathway via a known GPX4 inhibitor.
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