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Histone deacetylase ( HDAC )/phosphatidylinositol 3‐kinase ( PI 3K) dual inhibition is a promising strategy for the treatment of intractable cancers because of the advantages of overcoming potential resistance and showing synergistic effects. Therefore, development of an  HDAC / PI 3K dual inhibitor is reasonably attractive. Romidepsin ( FK 228, depsipeptide) is a potent  HDAC  inhibitor. We previously reported that depsipeptide and its analogs have an additional activity as  PI 3K inhibitors and are defined as  HDAC / PI 3K dual inhibitors. Subsequently, we identified  FK ‐A11 as the most potent analog and reported its biochemical, biological, and structural properties as an  HDAC / PI 3K dual inhibitor. In this study, we reveal the  in vitro  and  in vivo  efficacy of  FK ‐A11 in  HT 1080 fibrosarcoma and  PC 3 prostate cancer cell xenograft mouse models.  FK ‐A11 showed  in vivo  antitumor activity by both i.v. and i.p. administration in a dose‐dependent manner. In both xenograft models,  FK ‐A11 showed superior antitumor effects compared to other depsipeptide analogs in accordance with  in vitro  anti‐cell proliferation effects and the potency of  HDAC / PI 3K dual inhibition. In addition, we showed evidence of  HDAC / PI 3K dual inhibition accompanying antitumor efficacy in xenograft tumor tissues by immunohistochemistry. We also detailed pharmacokinetic characterization of  FK ‐A11 in mice. These findings will be essential for guiding further preclinical and clinical studies.

cancer science

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