Biochemical, biological and structural properties of romidepsin (FK228) and its analogs as novel HDAC/PI3K dual inhibitors

Abstract

Romidepsin (FK228, 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 FK228 and its analogs have an additional activity as phosphatidylinositol 3-kinase (PI3K) inhibitors, and are defined as HDAC/PI3K dual inhibitors. Because a combination of an HDAC inhibitor and a PI3K inhibitor induces apoptosis in human cancer cells in a synergistic manner, development of an HDAC/PI3K 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 FK228 and the other analogs in human cancer cells. In this study, we have characterized the biochemical, biological and structural properties of FK228 analogs as PI3K inhibitors. First, FK-A11 is an ATP competitive PI3K inhibitor. Second, FK-A11 is a pan-p110 isoform inhibitor. Third, FK-A11 selectively inhibits PI3K among 22 common cellular kinases. Fourth, conformational changes of FK228 analogs by reduction of an internal disulfide bond have no effect on PI3K inhibitory activity, unlike HDAC inhibitory activity. Finally, molecular modeling of PI3K-FK228 analogs and analyses of the binding affinities identified the structure that defines potency for PI3K inhibitory activity. These results prove our concept that a series of FK228 analogs are HDAC/PI3K dual inhibitors. These findings should help in the development of FK228 analogs as novel HDAC/PI3K dual inhibitors.

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…CUDC-907 is another dual-acting agent developed by the same research group to inhibit both HDACs and phosphoinositide 3-kinase (PI3K) (Qian et al 2012) and its clinical trials are underway for the treatment of lymphoma and multiple myeloma as well as advanced/relapsed solid tumors. Romidepsin (FK228, depsipeptide) is a potent Class I histone deacetylase inhibitor that has FDA approval for the treatment of cutaneous and peripheral T-cell lymphomas, and recent research demonstrated that FK228 and its analogs (FK-A5 and FK-A11) act as HDACs and PI3K dual inhibitors (Saijo et al 2012; Saijo et al 2015). …”

Antitumor activity and pharmacologic characterization of the depsipeptide analog as a novel histone deacetylase/ phosphatidylinositol 3‐kinase dual inhibitor

“…Although HDAC inhibitory activity is equally potent, the PI3K inhibitory activity is different among these analogs. We previously compared their inhibitory activities against HDAC and PI3K and identified FK‐A11 as the most potent HDAC/PI3K dual inhibitor . In the present study, we researched three compounds: FK‐A11, FK228, and FK‐A3.…”

“…To evaluate the kinase inhibition profile, we previously reported inhibitory activities of FK‐A11 for 22 kinases . In the present study, inhibitory activities of FK‐A11 were assayed further using a panel including 313 kinases.…”

“…In other words, FK228 and depsipeptide analogs have been identified as novel HDAC/PI3K dual inhibitors. Furthermore, we have identified and reported an analog FK‐A11 with potent HDAC/PI3K dual inhibitory activity . Here, we describe the in vitro and in vivo antitumor activity of FK‐A11 in human cancer cell line xenograft mouse models.…”

Romidepsin and the Zinc‐Binding Thiol Family of Natural Product HDAC Inhibitors

“…While the total synthesis routes are perhaps not competitive with fermentation for production of the natural products themselves, they are absolutely essential for the synthesis of unnatural analogues. Academic groups such as Ganesan [42] and Williams [43][44][45] as well as others including Luesch [46,47], Jiang [61], de Lera [62], Breit [48] and Katoh [49] have reported the synthesis and HDAC inhibitory activity of analogues. Summarising the data, some general conclusions can be drawn about the SAR of this compound class:…”