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Assays for Validating Histone Acetyltransferase Inhibitors
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Romidepsin (FK228), A Histone Deacetylase Inhibitor and its Analogues in Cancer Chemotherapy

Eftiola Pojani1, Daniela Barlocco2

  • 1Department of the Chemical-Toxicological and Pharmacological Evaluation of Drugs, Faculty of Pharmacy, Catholic University "Our Lady of Good Counsel", Tirana, Albania.

Current Medicinal Chemistry
|February 5, 2020
PubMed
Abstract

Insights

This study reviews novel histone deacetylase (HDAC) inhibitors based on Romidepsin (FK228) analogues. Some analogues show dual HDAC/PI3K inhibition, offering synergistic effects for cancer treatment.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Biology

Background:

  • Histone deacetylases (HDACs) are crucial enzymes involved in chromatin regulation.
  • Aberrant histone modifications are linked to cancer development, making HDAC inhibitors promising therapeutic agents.
  • Several HDAC inhibitors, including Romidepsin (FK228), are FDA-approved for cancer treatment.

Purpose of the Study:

  • To review structure-activity relationships of Romidepsin (FK228) analogues as HDAC inhibitors.
  • To investigate the potential of dual HDAC/PI3K inhibition by FK228 derivatives for enhanced anti-cancer effects.

Main Methods:

  • Literature search of PubMed, MEDLINE, CAPLUS, and SciFinder Scholar databases from 2015 to present.
  • Focus on studies detailing FK228 analogues, their HDAC inhibitory activity, and synergistic effects.
  • Analysis of structure-activity relationships and dual inhibition mechanisms.

Main Results:

  • Several FK228 analogues, including FK-A5, 22, 23, and FK-A11 (26), demonstrated significant activity against Class I HDACs and dose-dependent antitumor effects.
  • Compound 26 emerged as a potent HDAC/PI3K dual inhibitor, with IC50 values of 0.64 nM for HDAC1 and 6.7 μM for p110α.
  • Class I HDAC inhibitors are of significant interest due to their expression in various tumor types and potential for reduced side effects.

Conclusions:

  • Romidepsin analogues are effective anticancer agents.
  • Dual HDAC/PI3K inhibition by FK228 derivatives shows synergistic potential in inducing apoptosis in cancer cells.
  • Further research into FK228 analogues could lead to more potent tumor treatment options.
Keywords:
HDAC inhibitorsHDACsPI3Kapoptosisdual inhibitorsnovel anti-cancer therapiesstructureactivity relationships (SAR)

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