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Romidepsin ( FK 228, depsipeptide) is a potent histone deacetylase ( HDAC ) inhibitor that has  FDA  approval for the treatment of cutaneous and peripheral T‐cell lymphomas. We have previously reported that  FK 228 and its analogs have an additional activity as phosphatidylinositol 3‐kinase ( PI 3K) inhibitors, and are defined as  HDAC / PI 3K dual inhibitors. Because a combination of an  HDAC  inhibitor and a  PI 3K inhibitor induces apoptosis in human cancer cells in a synergistic manner, development of an  HDAC / PI 3K dual inhibitor will provide an attractive novel drug for cancer therapy. Using structure‐based optimization of the analogs,  FK ‐A11 was identified as the most potent analog.  FK ‐A11 inhibited phosphorylation of  AKT  and accelerated histone acetylation at lower concentrations, resulting in stronger cytotoxic effects than  FK 228 and the other analogs in human cancer cells. In this study, we have characterized the biochemical, biological and structural properties of  FK 228 analogs as  PI 3K inhibitors. First,  FK ‐A11 is an  ATP  competitive  PI 3K inhibitor. Second,  FK ‐A11 is a pan‐p110 isoform inhibitor. Third,  FK ‐A11 selectively inhibits  PI 3K among 22 common cellular kinases. Fourth, conformational changes of  FK 228 analogs by reduction of an internal disulfide bond have no effect on  PI 3K inhibitory activity, unlike  HDAC  inhibitory activity. Finally, molecular modeling of  PI 3K‐ FK 228 analogs and analyses of the binding affinities identified the structure that defines potency for  PI 3K inhibitory activity. These results prove our concept that a series of  FK 228 analogs are  HDAC / PI 3K dual inhibitors. These findings should help in the development of  FK 228 analogs as novel  HDAC / PI 3K dual inhibitors.

Biochemical, biological and structural properties of romidepsin ( FK 228) and its analogs as novel HDAC / PI 3K dual inhibitors