Rocilinostat (ACY-1215) is a selective inhibitor of HDAC6 with IC50 of 5 nM [1].
HDAC6 (histone deacetylase 6) is an enzyme which encoded by the HDAC6 gene and plays an important role in translational regulation, cell cycle progression and developmental events. It has been revealed that over-expression of HDAC6 is correlated with tumorigenesis and cell survival and HDAC6 also involves in cancer cells metastasis [2] [3].
Rocilinostat (ACY-1215) is a selective HDAC6 inhibitor. 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 [1]. In multiple myeloma cells, used ACY-125 as an adjuvant with carfilzomib triggered synergistic anti-MM effects, even in bortezomib-resistant cells which resulted in enhance cells apoptosis [2].
In mouse model with xenografted human MM cells, administration of ACY-125 only or with bortezomib could markedly delay tumor growth and the combination showed best efficacy [1].
It is also reported that ACY-1215 has minimal activity against HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2 (IC50 > 1μM), and has slight activity against HDAC8 (IC50 = 0.1μM) [1]. When tested with mouse xenografted MM cells, combination carfilzomib with ACY-1215 showed a decreased effect on tumor volume and cells apoptosis [2].
参考文献:
[1].?? ?Santo, L., et al., Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood, 2012. 119(11): p. 2579-89.
[2].?? ?Mishima, Y., et al., Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br J Haematol, 2015.
[3].?? ?Haakenson, J., et al., HDAC6-Dependent Functions in Tumor Cells: Crossroad with the MAPK Pathways. Crit Rev Oncog, 2015. 20(1-2): p. 65-81.
| Kinase experiment [1]: | |
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Inhibitory activities |
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 experiment [1]: | |
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Cell lines |
MM cells; PBMCs. |
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Preparation method |
Soluble in DMSO > 10 mM. 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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Reaction Conditions |
0.16, 0.8, 4, 20 nM; MM cells: 24 h, PBMCs: 48 h. |
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Applications |
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. |
| Animal experiment [1]: | |
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Animal models |
Male SCID mice inoculated subcutaneously with MM.1S cells. |
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Dosage form |
50 mg/kg; 5 days a week for 3 weeks; administrated orally. |
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Preparation method |
Dissolved in 10% DMSO in 5% dextrose in water |
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Applications |
In human MM xenograft mouse model, ACY-1215 (50 mg/kg) significantly delays tumor growth. Treatment mice with ACY-1215 plus bortezomib significantly prolonged overall survival (OS) and induces a significant accumulation of polyubiquitinated proteins. Treatment with ACY-1215 plus bortezomib is well tolerated and have no significant influence on the body weight. In female SCID-beige mice inoculated intravenously with MM.1S-LucNeo cells, treatment with ACY-1215 (75 mg/kg) and bortezomib (1.5 mg/kg) significantly inhibits tumor growth and prolongs OS. |
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Other notes |
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]. Santo L, Hideshima T, Kung AL, et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood, 2012, 119(11): 2579-2589. |
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