Background
ACY-241 is a new, selective and orally available inhibitor of HDAC6 [1][2].
Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from an ε-N-acetyl lysine on a histone, allowing the histones to wrap the DNA more tightly. HDAC6 plays an important role in transcriptional regulation and cell cycle progression.
ACY-241 is a new, selective and orally available HDAC6 inhibitor. In MM and MCL cells, the addition of ACY-241 to either lenalidomide (len) or pomalidomide (pom) resulted in synergistic increases in apoptosis and further reduced the expression of transcription factors MYC and IRF4 [1]. In multiple solid tumor cell lines, combination treatment with ACY-241 and paclitaxel resulted in enhanced inhibition of cell proliferation and increased cell death, compared with either single agent alone [2].
In MM xenograft model, combination treatment with ACY-241 and pomalidomide was well tolerated with no overt toxicity and significantly extended survival [1]. In xenograft models of pancreatic and ovarian cancer, combination treatment with ACY-241 and paclitaxel significantly increased mitotic cells with multipolar spindles. ACY-241 dose-dependently increased α-tubulin hyperacetylation [2].
参考文献:
[1].? Quayle SN, Almeciga-Pinto I, Tamang D, et al. Selective HDAC inhibition by ricolinostat (ACY-1215) or ACY-241 synergizes with IMiD? immunomodulatory drugs in Multiple Myeloma (MM) and Mantle Cell Lymphoma (MCL) cells. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research, 2015, Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5380.
[2].? Huang P, Almeciga-Pinto I, Jordan M, et al. Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models. In: Proceedings of the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, Massachusetts. Philadelphia (PA): AACR
Protocol
| Cell experiment [1]: |
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Cell lines
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A2780 ovarian cancer cells
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Preparation method
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The solubility of this compound in DMSO is >23.4mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.
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Reacting condition
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0.1, 0.3, 0.5, 1. 3 μM; dissolved in DMSO; 24 h
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Applications
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In A2780 ovarian cancer cells, ACY-241 (0.3 μM) increased hyperacetylation of α-tubulin, consistent with inhibition of the tubulin deacetylase HDAC6. Hyperacetylation of histone H3, a target of Class I HDACs, was only observed at doses above 1 μM. ACY-241 preferentially induced hyperacetylation of α-tubulin relative to H3K56.
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| Animal experiment [1]: |
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Animal models
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female athymic nude mice bearing MiaPaCa-2 pancreatic cancer xenografts
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Dosage form
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ACY-241: 50 mg/kg once daily for five days, followed by two days off, for three consecutive weeks; intraperitoneal injectionPaclitaxel: 10 mg/kg once daily for five consecutive days; intraperitoneal injection
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Application
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In female athymic nude mice bearing MiaPaCa-2 pancreatic cancer xenografts, ACY-241 (50 mg/kg) plus paclitaxel (10 mg/kg) inhibited tumor growth and did not result in body weight loss. ACY-241 was well tolerated in mice when dosed as a single agent and in combination with paclitaxel.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Huang P, Almeciga-Pinto I, Jordan M, et al. Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models. In: Proceedings of the 2015 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, Massachusetts. Philadelphia (PA): AACR
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