FK228 is a histone deacetylase (HDAC) inhibitor with potent in vivo antitumor activity, the clinical efficacy of which is under phase trials. FK228 is structurally distinct from other HDAC inhibitors and has no apparent functional group to interact with the residues in the enzyme active-site pocket. An internal disulfide bond of FK228 was found to be reduced by intracellular reducing activity to yield two free sulfhydryl groups, one of which is potentially accessible to the catalytic center zinc (see the image). The computer modeling suggests that the sulfur atom is located 3.12 Å apart from a water molecule bound to the zinc. The data indicate that FK228 serves as a prodrug to inhibit class I HDACs and is activated by reduction after uptake into the cells. For details, see the article by Furumai et al. on page 4916 of this issue.