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

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.