Metabolite elucidation of the Hsp90 inhibitor SNX-2112 using ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS)

1.The novel heat-shock protein 90 inhibitor SNX-2112 is a promising drug candidate for treating various types of cancers. Here we aim to determine the metabolic pathways of SNX2112 in rats in vivo and in humans in vitro. 2. Metabolite identification was performed using ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method. In vitro metabolism studies were performed using liver and intestine microsomes, as well as recombinant human cytochrome P450 (CYP) enzymes. 3. Analysis of rat plasma, urine, and feces revealed a total of eight metabolites, one reductive metabolite (M1), one structurally unknown metabolite (M2), and six mono-oxidative metabolites (M3-1, M3-2, M3-3, M3-4, M3-5, and M3-6). The reduction, M2, and monooxidation pathways were responsible for 0.8 +/- 0.3 %, 18.3 +/- 9.1 %, and 39.4% +/- 6.1 of SNX2112 clearance from rats, respectively. 4. SNX-2112 was subjected to the same types of metabolism in human liver and intestine microsomes. Reaction phenotyping showed that CYP3A4, 3A5, 2D6, and 1A1 were mainly responsible for SNX-2112 metabolism. 5. In conclusion, we have elucidated the metabolic pathways of SNX-2112 and highlighted that metabolism was the predominant pathway for its clearance. Better understanding of SNX2112 metabolism should facilitate the drug development of this promising anti-cancer agent.