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Romidepsin (FK228), A Histone Deacetylase Inhibitor and its Analogues in Cancer Chemotherapy


Eftiola Pojani* and Daniela Barlocco   Pages 1 - 14 ( 14 )


Background: Human HDACs represent a group of enzymes able to modify histone and non-histone proteins, which interact with DNA to generate chromatin. The correlation between irregular covalent modification of histones and tumor development has been proven over the last decades. Therefore, HDAC inhibitors are considered as potential drugs in cancer treatment. Romidepsin (FK228), Belinostat (PXD-101), Vorinostat (SAHA), Panobinostat (LBH-589) and Chidamide were approved by FDA as novel antitumor agents.

Objective: The aim of this review article is to highlight the structure-activity relationships of several FK228 analogues as HDAC inhibitors. In addition, the synergistic effects of a dual HDAC/PI3K inhibition by some derivatives have been investigated.

Materials and Methods: PubMed, MEDLINE, CAPLUS, SciFinder Scholar database were considered by selecting articles which fulfilled the objectives of this review, dating from 2015 till present time.

Results: HDAC inhibitors have a significant role in cancer pathogenesis and evolution. Class I HDAC isoformrs are expressed in many tumor types, therefore, potent and selective Class I HDAC inhibitors are of great interest as candidate therapeutic agents with limited side effects. By structurebased optimization, several FK228 analogues [15 (FK-A5), 22, 23, 26 (FK-A11)] were identified, provided with significant activity against Class I HDAC enzymes and dose dependent antitumor activity. Compound 26 was recognized as an interesting HDAC/PI3K dual inhibitor (IC50 against p110α of 6.7 μM while for HDAC1 inhibitory activity IC50 was 0.64 nM).

Conclusion: Romidepsin analogues HDAC inhibitors have been confirmed as useful anticancer agents. In addition, dual HDAC/PI3K inhibition showed by some of them exhibited synergistic effects in inducing apoptosis in human cancer cells. Further studies on FK228 analogues may positively contribute to the availability of potent agents in tumor treatment.


HDACs, apoptosis, HDAC inhibitor, PI3K, dual inhibitors, novel anti-cancer therapies, SAR.


Department of the Chemical-Toxicological and Pharmacological Evaluation of Drugs, Faculty of Pharmacy, Catholic University “Our Lady of Good Counsel”, Tirana, Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Milan, L. Mangiagalli 25 - 20133 Milan

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