Romidepsin ( FK 228) and its analogs directly inhibit phosphatidylinositol 3‐kinase activity and potently induce apoptosis as histone deacetylase/phosphatidylinositol 3‐kinase dual inhibitors

Activation of phosphatidylinositol 3‐kinase ( PI 3 K ) signaling is involved in carcinogenesis and cancer progression. The PI 3 K inhibitors are considered candidate drugs for cancer treatment. Here, we describe a drug screening system for novel PI 3 K inhibitors using S accharomyces cerevisiae strains with deleterious mutations in the ATP ‐binding cassette transporter genes, because wild‐type S .  cerevisiae uses drug efflux pumps for reducing intracellular drug concentrations. By screening the chemical library of the S creening C ommittee of A nticancer D rugs, we identified the histone deacetylase ( HDAC ) inhibitor romidepsin ( FK 228) and its novel analogs. In vitro PI 3 K activity assays confirmed that these compounds directly inhibit PI 3 K activity at μM‐range concentrations. FK ‐ A 5 analog was the most potent inhibitor. Western blotting revealed that these compounds inhibit phosphorylation of protein kinase B and downstream signaling components. Molecular modeling of the PI 3 K – FK 228 complex indicated that FK 228 binds to the ATP ‐binding pocket of PI 3 K . At μM‐range concentrations, FK 228 and FK ‐ A 5 show potent cytotoxicity, inducing apoptosis even in HDAC inhibitor‐resistant cells. Furthermore, HDAC / PI 3 K dual inhibition by FK 228 and FK ‐ A 5 at μM‐range concentrations potentiates the apoptosis induction, mimicking the effect of combining specific HDAC and PI 3 K inhibitors. In this study, we showed that FK 228 and its analogs directly inhibit PI 3 K activity and induce apoptosis at μM‐range concentrations, similar to HDAC / PI 3 K dual inhibition. In future, optimizing the potency of FK 228 and its analogs against PI 3 K may contribute to the development of novel HDAC / PI 3 K dual inhibitors for cancer treatment.