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

Cancer Science

Ken Saijo³  Jin Imamura³  Koichi Narita²  Akifumi Oda¹  Hideki Shimodaira³  Tadashi Katoh² 

[1] Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan;Laboratory of Synthetic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai, Japan;Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

关键词: Drug development;    dual inhibitor;    HDAC;    PI3K;    romidepsin;   

DOI  :  10.1111/cas.12585

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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