The Discovery of the Mode of Action of Nitisinone

Abstract

This review briefly discusses the discovery of the mode of action of the triketone herbicide, 2-(2-nitro-4-trifluormethylbenzoyl)-1,3-cyclohexanedione and its use as a drug Nitisinone for the treatment of inborn errors of tyrosine metabolism. Nitisinone is a potent reversible tight-binding inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, involved in the catabolism of the amino acid tyrosine. Nitisinone is used to treat the rare disease hereditary tyrosinaemia type 1 where the last enzyme in the breakdown of tyrosine, fumarylacetoacetase is deficient. Nitisinone is also used to treat patients with alkaptonuria where the enzyme homogentisic acid oxidase is deficient. Articles in this issue discuss metabolites of tyrosine catabolism in healthy patients and those with alkaptonuria.

Discovery of New Fusobacterium nucleatum Inhibitors to Attenuate Migratory Capability of Colon Cancer Cells by the Drug Repositioning Strategy

“…Nitisinone ( 7) is a small molecule inhibitor of 4hydroxyphenylpyruvate dioxygenase (HPPD), which was initially developed as an herbicide and later found to treat hereditary type 1 tyrosinemia in the absence of fumarylacetoacetate hydrolase (FAH). 46 In our anti-F. nucleatum assay, nitisinone exhibited moderate inhibitory potency with a MIC 50 value of 8 μg/mL, which is the first report of nitisinone as an antibacterial agent. Antihistaminics are widely used for various indications during microbial infection.…”

“…Terfenadine ( 10 ) exhibited moderate antimicrobial activity against S. aureus , and also inhibited F. nucleatum (MIC 50 = 16 μg/mL).…”

“…Nitisinone ( 7 ) is a small molecule inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), which was initially developed as an herbicide and later found to treat hereditary type 1 tyrosinemia in the absence of fumarylacetoacetate hydrolase (FAH) . In our anti-F.…”

“…exhibited moderate antimicrobial activity against S. aureus46,48 and also inhibited F. nucleatum (MIC 50 = 16 μg/mL).Based on the above active drug, we summarize the pharmacophore features among the active drugs. Generally, drugs containing nitro-(hetero)aromatic moiety including dimetridazole, ronidazole, fexinidazole, furazolidone, and nifurtimox demonstrated moderate to good anti-F. nucleatum activity (MIC 50 range: 1−16 μg/mL), while saccharide…”

Applying real-world data from expanded-access (“compassionate use”) patients to drug development

“…EA evidence alone was used in an additional four examples: combined sodium phenylacetate and sodium benzoate [16] to treat acute hyperammonaemia in patients with a rare urea cycle disorder; uridine triacetate [17] following overdoses with 5fluorouracil or capecitabine; cholic acid [18,19] to treat bile acid disorders; and nitisinone [20][21][22] to treat hereditary tyrosinaemia type 1.…”