product name Rocilinostat (ACY-1215)
Description: Rocilinostat (ACY-1215) is a selective HDAC6 inhibitor with IC50 of 5 nM in a cell-free assay. It is >10-fold more selective for HDAC6 than HDAC1/2/3 with slight activity against HDAC8, and with minimal activity against HDAC4/5/7/9/11, Sirtuin1, and Sirtuin2. When tested with human MM cell lines (MM.1S), treatment with ACY-1215 in increasing dose for 6 hours increased acetylated α-tubulin at a concentration of 0.62μM via inhibiting HDAC6. ACY-125 was used as an adjuvant with carfilzomib triggered synergistic anti-MM effects, even in bortezomib-resistant cells which resulted in enhance cells apoptosis.
References: Blood. 2012 Mar 15;119(11):2579-89.
433.5
Formula
C24H27N5O3
CAS No.
1316214-52-4
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 86 mg/mL (198.4 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
2% DMSO+30% PEG 300+ddH2O: 5 mg/mL
Synonyms
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19425017
| In Vitro |
In vitro activity: ACY-1215 is a hydroxamic acid derivative. ACY-1215 is 12-, 10-, and 11-fold less active against HDAC1, HDAC2, and HDAC3 (class I HDACs), respectively. ACY-1215 has minimal activity (IC50 > 1μM) against HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2, and has slight activity against HDAC8 (IC50 = 0.1μM). The IC50 values for ACY-1215 for T-cell toxicity is 2.5μM. ACY-1215 overcomes tumor cell growth and survival conferred by BMSCs and cytokines in the BM milieu. ACY-1215 in combination with bortezomib induces synergistic anti-MM activity. ACY-1215 induces potent acetylation of α-tubulin at very low doses and triggers acetylation of lysine on histone H3 and histone H4 only at higher doses, confirming its specific inhibitory effect on HDAC6 activity. Kinase Assay: ACY-1215 was dissolved and subsequently diluted in assay buffer [50 mM HEPES, pH 7.4, 100 mM KCl, 0.001% Tween-20, 0.05% BSA, and 20 μM tris(2-carboxyethyl)phosphine] to 6-fold the final concentration. HDAC enzymes were diluted to 1.5-fold of the final concentration in assay buffer and pre-incubated with ACY-1215 for 10 minutes before the addition of the substrate. The amount of FTS (HDAC1, HDAC2, HDAC3, and HDAC6) or MAZ-1675 (HDAC4, HDAC5, HDAC7, HDAC8, and HDAC9) used for each enzyme was equal to the Michaelis constant (Km), as determined by a titration curve. FTS or MAZ-1675 was diluted in assay buffer to 6-fold the final concentration with 0.3 μM sequencing grade trypsin. The substrate/trypsin mix was added to the enzyme/compound mix and the plate was shaken for 60 seconds and then placed into a SpectraMax M5 microtiter plate reader. The enzymatic reaction was monitored for release of 7-amino-4-methoxy-coumarin over 30 minutes, after deacetylation of the lysine side chain in the peptide substrate, and the linear rate of the reaction was calculated. HDAC11, sirtuin1, and sirtuin2 assays were performed by Cerep. Cell Assay: ACY-1215 induces less cytotoxicity in PHA-stimulated or unstimulated PBMCs. In purified CD4+ T cells, ACY-1215 induces toxicity with IC50 value of 2.5 μM. In MM cell lines, ACY-1215 dose-dependently decreases viability with IC50 value of 2-8 μM and induces significant cytotoxicity. In MM.1S cells, ACY-1215 dose-dependently reduces DNA synthesis of MM cells adherent to BMSCs and also inhibits growth induced by IL-6 and IGF-1. |
|---|---|
| In Vivo | ACY-1215 in combination with bortezomib triggered more significant anti-MM activity than either agent alone in suppressing tumor growth and prolonging survival in both plasmacytoma model and disseminated MM model without significant adverse effects. ACY-1215 is readily absorbed by tumor tissue. Moreover, the drug does not accumulate in tumor tissue, as evidenced by the parallel decline of acetylated α-tubulin in blood cells and tumor tissue by 24 hours after dose. |
| Animal model | Male SCID mice inoculated subcutaneously with MM.1S cells. |
| Formulation & Dosage | Formulated in 10% DMSO in 5% dextrose in water; 50 mg/kg; 5 days a week for 3 weeks; Oral administration. |
| References | Blood. 2012 Mar 15;119(11):2579-89. |
