Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1.

INTRODUCTION: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1. RESULTS: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. CONCLUSION: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.

Comparison between the effects of torsemide and furosemide on the renin-angiotensin-aldosterone system of normal dogs.

INTRODUCTION/OBJECTIVES: We hypothesized that torsemide and furosemide, at approximately equipotent dosages (similar diuresis), would have comparable effects on the circulating renin-angiotensin-aldosterone system. ANIMALS, MATERIALS AND METHODS: Six, healthy, middle-aged, male Beagles were randomized to receive torsemide (0.1 mg/kg PO q 12 h), furosemide (2.0 mg/kg PO q 12 h), or placebo for 10 days during three separate periods, separated by a 10-day washout period, in a crossover design. Blood was collected on days 1, 5, and 9 and 24-h urine collection ended on days 2, 6, and 10. After repeated measures analysis and Bonferonni correction, variables with an adjusted p<0.05 were investigated further, using Tukey's method. RESULTS: Twenty-four-hour urine production differed significantly between the diuretics only on day 10, with torsemide causing a 38% greater diuresis than furosemide. There was, however, no significant difference in average 3-day diuresis. There were no significant differences between diuretics in the 24-h urinary excretion of sodium, chloride, or potassium, though furosemide caused less kaliuresis than torsemide. Serum renin, angiotensin II, and aldosterone and the urine aldosterone-to-creatinine ratio were significantly increased in the diuretic groups, as compared to placebo on days 5/6 and 9/10. There were no significant differences in these values between diuretics. Creatinine and blood urea nitrogen concentrations rose comparably in the diuretic groups, remaining within reference intervals in all dogs. CONCLUSIONS: At approximately equipotent dosages (20:1), torsemide and furosemide produced comparable renin-angiotensin-aldosterone system activation. Torsemide's similar potassium excretion profile to furosemide decreases support for a hypothesized mineralocorticoid-receptor blocking capability.