Trifluoromethyl ketones as inhibitors of histone deacetylase

Frey, Robin R.; Wada, Carol K.; Garland, Robert B.; Curtin, Michael L.; Michaelides, Michel; Li, Junling; Pease, Lori J.; Glaser, Keith B.; Marcotte, Patrick A.; Bouska, Jennifer J.; Murphy, Shannon S.; Davidsen, Steven K.

doi:10.1016/s0960-894x(02)00754-0

Cited by 126 publications

(52 citation statements)

References 27 publications

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“…MS-275 and CI-994) (Saito et al, 1999;Prakash et al, 2001) and electrophilic ketone (e.g. trifluoromethyl ketones and a-ketoamides) (Frey et al, 2002) classes of HDAC inhibitors are less potent than hydroxamates and cyclic tetrapeptides, exhibiting HDAC inhibition activity in the micromolar concentration range. The least potent class of HDAC inhibitors is the aliphatic acid group of compounds that are effective inhibitors of HDAC activity at millimolar concentrations (Phiel et al, 2001;Boivin et al, 2002).…”

Section: Cellular Effects Of Hdac Inhibitorsmentioning

confidence: 99%

Modulation of cellular radiation responses by histone deacetylase inhibitors

Karagiannis

El‐Osta

2006

Oncogene

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Histone deacetylase (HDAC) inhibitors are emerging as a new class of targeted cancer chemotherapeutics. Several HDAC inhibitors are currently in clinical trials and promising anticancer effects at well-tolerated doses have been observed for both hematologic and solid cancers. HDAC inhibitors have been shown to induce cell-cycle and growth arrest, differentiation and in certain cases apoptosis in cell cultures and in vivo. However, it is known that these compounds induce varying responses in different cells and biological settings, and identifying their precise mechanisms of action is an area of great interest. Important findings are continually expanding our understanding of the cellular effects of HDAC inhibitors and recent studies will be briefly outlined in this review. In addition to their intrinsic anticancer properties, numerous studies have demonstrated that HDAC inhibitors can modulate cellular responses to other cytotoxic modalities including ionizing radiation, ultraviolet radiation and chemotherapeutic drugs. Hence, there is a growing interest in potential clinical use of HDAC inhibitors in combination with conventional cancer therapies. In this review, the interaction of HDAC inhibitors with other anticancer agents is discussed. The focus of the article is on the different mechanisms by which HDAC inhibitors enhance the sensitivity of cells to the effects of ionizing radiation.

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Section: Cellular Effects Of Hdac Inhibitorsmentioning

confidence: 99%

Modulation of cellular radiation responses by histone deacetylase inhibitors

Karagiannis

El‐Osta

2006

Oncogene

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“…A common structural feature of these inhibitors is the existence of a hydrophobic head that is separated from the zinc-binding group through a hydrophobic tether that extends 5 or 6 carbons long. Several nonhydroxamate inhibitors have also been identified, including short-chain fatty acids [21,22], MS-27-275 [23], trifluoromethyl ketones [24], phosphorus-based compounds [25], bisulfide bromotyrosine derivatives [26], and α-keto amides [27]. Still in progress are the synthetic studies to optimize inhibitory strength, stability, and bioavailability.…”

Section: Introductionmentioning

confidence: 99%

Homology modeling, force field design, and free energy simulation studies to optimize the activities of histone deacetylase inhibitors

Park

Lee

2004

J Comput Aided Mol Des

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As an effort to develop therapeutics for cancer treatments, a number of effective histone deacetylase inhibitors with structural diversity have been discovered. To gain insight into optimizing the activity of an identified lead compound, a computational protocol sequentially involving homology modeling, docking experiments, molecular dynamics simulation, and free energy perturbation calculations was applied for rationalizing the relative activities of known histone deacetylase inhibitors. With the newly developed force field parameters for the coordination environment of the catalytic zinc ion in hand, the computational strategy proved to be successful in predicting the rank orders for 12 derivatives of three hydroxamate-based inhibitor scaffolds with indole amide, pyrrole, and sulfonamide moieties. The results showed that the free energy of an inhibitor in aqueous solution should be an important factor in determining the binding free energy. Hence, in order to enhance the inhibitory activity by adding or substituting a chemical group, the increased stabilization in solution due to the structural changes must be overcome by a stronger enzyme-inhibitor interaction. It was also found that to optimize inhibitor potency, the hydrophobic head of an inhibitor should be elongated or enlarged so that it can interact with Pro29 and His28 that are components of the flexible loop at the top of the active site.

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“…In an attempt to move away from the hydroxamic acid zinc binding group, which is known to causes poor pharmacokinetics as a result of hydrolysis or glucuronidation, the group at Abbott searched for alternative zinc chelators culminating in the development of a series of electrophilic ketone HDACis (Figure 9.12) [64][65][66]. Subsequently, a group at IRBM developed a related series of thiophene trifluoromethyl ketones and showed these to be selective class II HDACis [12].…”

Section: Electrophilic Ketonesmentioning

confidence: 99%

“…The trifluoromethyl ketone analog of SAHA (56) was synthesized and shown to display weak but measurable HDAC inhibitory activity, IC 50 ¼ 6.7 mM. Subsequently, these trifluoromethyl ketones were further optimized with changes to the lipophilic tether and the capping groups in order to develop more potent analogs, such as 6 which was shown to be a modestly active HDACi (IC 50 ¼ 310 nM) but unfortunately displayed only weak cellular activity (IC 50 ¼ 4.2 mM against HT1080 fibrosarcoma cells) [64]. The electrophilic carbonyl group is required as the corresponding methyl ketones are inactive.…”

Section: Electrophilic Ketonesmentioning

confidence: 99%

Histone Deacetylase Inhibitors

Jones

2009

Methods and Principles in Medicinal Chemistry

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Trifluoromethyl ketones as inhibitors of histone deacetylase

Cited by 126 publications

References 27 publications

Modulation of cellular radiation responses by histone deacetylase inhibitors

Modulation of cellular radiation responses by histone deacetylase inhibitors

Homology modeling, force field design, and free energy simulation studies to optimize the activities of histone deacetylase inhibitors

Histone Deacetylase Inhibitors

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