In vitro: In cell lines from multiple solid tumor lineages, combination treatment with ACY-241 and paclitaxel enhances inhibition of proliferation and increases cell death relative to either single agent alone. Combination treatment with ACY-241 and paclitaxel also results in more frequent occurrence of mitotic cells with abnormal multipolar spindles and aberrant mitoses, and is associated with increased frequency of abnormal multipolar mitotic spindle formation, induction of aneuploidy, and increased cell death. In A2780 ovarian cancer cells, 24 hour treatment with 300 nM ACY-241 results in increased hyperacetylation of α-tubulin, consistent with inhibition of the tubulin deacetylase HDAC6. Low exposures of ACY-241 result in selective inhibition of HDAC6, while higher exposures lead to inhibition of Class I HDAC isozymes. In vivo: ACY-241 has a favourable safety profile than non-selective pan-HDAC inhibitors. It has the potential for a substantially reduced side effect profile versus current nonselective HDAC inhibitor drug candidates due to reduced potency against Class I HDACs while retaining the potential for anticancer effectiveness.
|Cell lines||A2780 ovarian cancer cells|
|Preparation method||A2780 cells are cultured with vehicle or a range of ACY-241 concentrations for 24 hours prior to immunoblotting.|
|Concentrations||0.1, 0.3, 0.5, 1, 3 μM|
|Incubation time||24 h|
|Animal models||Female athymic nude mice (Crl:NU(NCr)-Foxn1nu)|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||93 mg/mL in DMSO|
Enhancement of pomalidomide anti-tumor response with ACY-241, a selective HDAC6 inhibitor.
North BJ, et al. PLoS One. 2017 Mar 6;12(3):e0173507. PMID: 28264055.
Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models.
Huang P, et al. Oncotarget. 2017 Jan 10;8(2):2694-2707. PMID: 27926524.
Deacetylase inhibitors as a novel modality in the treatment of multiple myeloma.
Richardson PG, et al. Pharmacol Res. 2017 Mar;117:185-191. PMID: 27884726.
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Chidamide is a low nanomolar inhibitor of HDAC1, 2, 3, and 10, the HDAC isotypes well documented to be associated with the malignant phenotype with IC50 values of 95, 160, 67, 78 nM for HDAC1, 2, 3, 10 respectively.
TMP195 is a selective, first-in-class, class IIa HDAC inhibitor with IC50 of 300 nM in cell-based class IIa HDAC assays.
WT-161 is a potent and selective HDAC6 inhibitor with an IC50 of 0.40 nM.
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