Citarinostat

Biological Activity

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.

Protocol

Cell Experiment
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 Experiment
Animal models	Female athymic nude mice (Crl:NU(NCr)-Foxn1nu)
Formulation
Dosages	50 mg/kg
Administration	i.p.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

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 K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

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.