Therapeutics: Histone deacetylase (HDAC); nitric oxide (NO)

In vitro and mouse studies identified an NO-donating HDAC inhibitor that could help treat cancer. Chemical synthesis and in vitro testing of hydroxamic acid analogs coupled to NO-donating functional groups identified a lead compound that inhibited HDAC enzymatic activity in HeLa cells more potently than vorinostat (IC50 values 0.038 and 0.11 μM, respectively) and inhibited proliferation in human leukemia, breast, colorectal and other cancer cell lines more potently than vorinostat. In a xenograft mouse model of erythroid acute leukemia, the lead compound decreased tumor growth by 48% compared with vehicle, whereas vorinostat decreased tumor growth by 39%. Next steps include pharmacokinetic and mechanistic studies of the lead compound...