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Histone deacetylase inhibitors: the Abbott experience
1Abbott Laboratories, R47J/AP10, 100 Abbott Park Rd, Abbott Park, IL 60064-6100, USA. mike.curtin@abbott.com
Current Medicinal Chemistry
|October 8, 2003
Summary
Abbott developed novel alpha-ketoamide histone deacetylase (HDAC) inhibitors. These compounds show potent enzymatic and cellular activity, with measurable anti-tumor effects, offering a promising new avenue for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Histone deacetylase inhibitors (HDACi) are investigated as anti-cancer agents.
- Abbott identified A-161906, a biaryl hydroxamate, as an inhibitor of selected HDACs.
- HDACs function in multi-protein complexes, complicating selectivity studies.
Purpose of the Study:
- To develop novel small molecule HDAC inhibitors with improved anti-cancer properties.
- To explore alternative moieties to the hydroxamic acid group for enhanced efficacy.
Main Methods:
- Synthesis and evaluation of hydroxamic acid analogs, trifluoromethyl ketones, ketooxazoles, and alpha-ketoamides.
- Assays included enzymatic inhibition, antiproliferation (HT1080, MDA435 cells), and in vivo anti-tumor activity.
- siRNA gene knockdown studies informed the understanding of HDAC function.
Main Results:
- Hydroxamic acids showed potent activity but poor pharmacokinetics and marginal anti-tumor effects.
- Trifluoromethyl ketone and ketooxazole replacements yielded modest cellular and in vivo activity.
- Alpha-ketoamide derivatives demonstrated potent HDAC inhibition (IC50 as low as 3 nM), excellent cellular activity (IC50 < 0.2 microM), and measurable anti-tumor effects.
Conclusions:
- Alpha-ketoamides represent a promising scaffold for developing potent and effective HDAC inhibitors.
- These novel compounds exhibit significant potential for anti-cancer applications.