Teach an old dog new tricks: the story of nitroxoline

Nitroxoline is a wide spectrum antibiotic that has been used in many countries (e.g., Germany, Taiwan, South Africa) for about fifty years. Recently, Asieris Pharmaceuticals (亚虹医药) initiated a Phase II trial (CTR20131716) to test nitroxoline (APL-1202) in non-muscle invasive bladder cancer. The NFPFC has granted Major Drug Invention Program of China’s 12th Five-year Plan designation to nitroxoline.

The antiangiogenic activity of nitroxoline was discovered by Jun Liu who received his undergraduate degree from Nanjing University in 1983 and now is a professor of pharmacology and molecular sciences at Johns Hopkins University. His research focuses on using old drugs to treat new diseases.

Jun Liu’s team identified nitroxoline as a MetAP2 inhibitor from a target-based high-throughput screen of 175000 compounds[1]. At the same time, they tested 2687 approved drugs (Johns Hopkins Drug Library) in HUVEC cells through a cell-based screening, and nitroxoline stood out again. Finally, Jun Liu concluded that nitroxoline inhibits HUVEC proliferation (IC50=1.9 μM) through dual inhibition of MetAP2 (IC50=54.8 nM) and SIRT1/2 (IC50= 20.2 μM, 15.5 μM).

The team tested nitroxoline in breast cancer (HCC1954) xenografts at the dose of 60 mg/kg. A 60% inhibition of tumor volume and a 43% inhibition of tumor weight were noted on day 30. Because more than 70% of nitroxoline was found in urine after oral dosing[2], they tested nitroxoline in mice with bladder cancer (KU7-luc) at the dose of 30 mg/kg. Nitroxoline showed a statistically significant inhibition of bladder tumor growth.

Actually, Jun Liu has designed and synthesized a series of derivatives derived from nitroxoline[3]. Several compounds inhibited HUVEC growth with sub-micromolar IC50, but did not affect MetAP2 or SIRT1, in contrast to the previous hypothesis. Asieris selected nitroxoline as clinical candidate without further optimization. Moreover, Kangrun Pharmaceuticals (康润医药) has filed a patent application (CN103319404) covering a list of nitroxoline derivatives.

The recommended dosage of nitroxoline in adults with urinary tract infections is 600 mg/day. At the dose of 400 mg/day, 10 µM of nitroxoline could be found in urine, which is high enough to inhibit angiogenesis in patients with bladder cancer. Asieris’ Phase II doses were 300-600 mg/day.

[1] J Natl Cancer Inst. 2010, 102(24), 1855-1873.

[2] Int J Clin Pharmacol Biopharm. 1979, 17(12), 476-481.

[3] Org Biomol Chem. 2012, 10(15), 2979-2992.

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