The 19th century Romantic poet, Lord Byron, who died a committed freedom fighter in the Greek War of Independence against the Ottomans, was famously described by his lover, Lady Caroline Lamb, as “mad, bad, and dangerous to know.”
Following in the footsteps of the inimitable Lord Byron, the original rebel with a cause, lead EpicentRx small molecule, RRx-001 (nibrozetone), also one-of-a-kind, is, “mad, bad, and either delightful or dangerous to NO” depending on the context. The NO, in this case, stands for nitric oxide, which RRx-001 releases but only under poorly oxygenated and acidic conditions that are common to several disease states.
Under these hypoxic/acidic conditions, where nitric oxide levels are often severely deficient and blood flow is compromised because NO acts as a vasodilator to widen or dilate blood vessels, RRx-001 fragments and releases its nitro groups, self-sacrificing to deliver, not freedom like Lord Byron, but nitric oxide.
In addition to being a vasodilator, NO acts as a broad-spectrum antimicrobial agent and a potent antioxidant that combines with and scavenges or neutralizes several free radicals. Partly for these reasons, RRx-001 is “delightful to NO”, being experimentally highly active in disease states and conditions where NO production and levels are dysfunctional. These include hypertension, atherosclerosis, pulmonary hypertension, adult respiratory distress syndrome, heart failure, myocardial infarction, stroke, type 2 diabetes, severe oral mucositis, hemorrhagic shock, COVID-19, malaria, and kidney failure among others.
The flip side is that the additional delivery of nitric oxide from RRx-001 in tumors where NO levels are already usually at maximal levels serves to push them over the edge into toxicity and cell death.
Ultimately, then, for tumors—and only for tumors—this makes RRx-001 mad, bad, and dangerous to NO.