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Synthesis and evaluation of novel dual BRD4/HDAC inhibitors
Seika Amemiya1, Takao Yamaguchi1, Yuichi Hashimoto1
1Institute of Molecular and Cellular, Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Abstract:
Epigenetic regulation of gene expression via histone acetylation modulates many cellular processes, including apoptosis, the cell cycle, cell growth and differentiation, and inhibitors are promising drug candidates. We have previously developed inhibitors of BRD4, which recognizes acetylated lysine residue on histones and recruits transcription elongation factor to the transcription start site, while inhibitors of histone deacetylase (HDAC), which catalyzes the removal of acetyl groups on histones, are already in clinical use for cancer treatment. Based on the idea that polypharmacological agents with multiple targets would have a more robust action, we set out to develop dual BRD4/HDAC inhibitors. Here, we describe the design and synthesis of N6-[2-(7-hydroxyamino-7-oxoheptyloxy)benzoyl]adenine (5d) as a BRD4/HDAC dual inhibitor. This compound showed HL-60 cell growth-inhibitory and apoptosis-inducing activity, as well as all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation-enhancing activity, and c-MYC production-inhibitory activity. Interestingly, it also showed growth-inhibitory activity towards BRD4 inhibitor-resistant cells.
Insights
Researchers developed a dual BRD4/HDAC inhibitor, compound 5d, which shows potent anti-cancer effects. This novel agent effectively inhibits cancer cell growth and promotes apoptosis, even in resistant cell lines.
Area of Science:
- Epigenetics and Cancer Therapeutics
- Molecular Biology and Drug Discovery
Background:
- Epigenetic modifications, such as histone acetylation, regulate critical cellular processes and are key targets for cancer therapy.
- Bromodomain-containing protein 4 (BRD4) inhibitors and histone deacetylase (HDAC) inhibitors are established therapeutic strategies.
- Polypharmacology, targeting multiple pathways simultaneously, offers potential for more robust anti-cancer actions.
Purpose of the Study:
- To design and synthesize novel dual inhibitors targeting both BRD4 and HDAC.
- To evaluate the anti-cancer efficacy of a lead dual inhibitor, N6-[2-(7-hydroxyamino-7-oxoheptyloxy)benzoyl]adenine (5d).
Main Methods:
- Chemical synthesis of compound 5d.
- In vitro evaluation of compound 5d's effects on HL-60 leukemia cells.
- Assessment of compound 5d's activity against BRD4 inhibitor-resistant cells.
Main Results:
- Compound 5d demonstrated significant HL-60 cell growth inhibition and apoptosis induction.
- The dual inhibitor enhanced all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation.
- Compound 5d effectively inhibited c-MYC production and exhibited anti-proliferative activity in BRD4 inhibitor-resistant cells.
Conclusions:
- N6-[2-(7-hydroxyamino-7-oxoheptyloxy)benzoyl]adenine (5d) is a potent BRD4/HDAC dual inhibitor with promising anti-cancer properties.
- This dual-targeting strategy is effective against leukemia cells and overcomes resistance mechanisms associated with BRD4 inhibition.
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