Rocilinostat (ACY1215; Ricolinostat)

Alias: Ricolinostat; Rocilinostat; ACY 1215; ACY1215; ACY-1215
Cat No.:V0271 Purity: = 99.55%
Rocilinostat (formerly Ricolinostat; ACY-1215), an investigational drug, is a potent, orally bioavailable and selective HDAC6 inhibitor with potential anticancer activity.
Rocilinostat (ACY1215; Ricolinostat) Chemical Structure CAS No.: 1316214-52-4
Product category: HDAC
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: = 99.55%

Product Description

Rocilinostat (formerly Ricolinostat; ACY-1215), an investigational drug, is a potent, orally bioavailable and selective HDAC6 inhibitor with potential anticancer activity. In a cell-free experiment, it inhibits HDAC6 with an IC50 of 5 nM, exhibits over ten-fold selectivity for HDAC6 over HDAC1/2/3, and exhibits negligible or no activity against HDAC8

Biological Activity I Assay Protocols (From Reference)
Targets
HDAC6 ( IC50 = 4.7 nM ); HDAC2 ( IC50 = 48 nM ); HDAC3 ( IC50 = 51 nM ); HDAC1 ( IC50 = 58 nM ); HDAC8 ( IC50 = 100 nM ); HDAC7 ( IC50 = 1400 nM ); HDAC5 ( IC50 = 5000 nM ); HDAC4 ( IC50 = 7000 nM )
ln Vitro

In vitro activity: ACY-1215 is a derivative of hydroxamic acid. ACY-1215 exhibits a 12-, 10-, and 11-fold reduction in activity against class I HDACs, namely HDAC1, HDAC2, and HDAC3. ACY-1215 exhibits negligible activity (IC50 > 1μM) towards HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2, and demonstrates mild activity (IC50 = 0.1μM) towards HDAC8. ACY-1215 has an IC50 value of 2.5μM for T-cell toxicity. ACY-1215 suppresses the growth and survival of tumor cells that are provided by BMSCs and cytokines within the BM milieu. ACY-1215 and bortezomib together produce synergistic anti-MM activity. ACY-1215 has been shown to specifically inhibit HDAC6 activity because it causes strong acetylation of α-tubulin at very low doses and only at higher doses causes acetylation of lysine on histone H3 and H4. [1]

ln Vivo
ACY-1215 and bortezomib together produced a greater anti-MM activity than either drug alone did in terms of inhibiting tumor growth and extending survival without appreciable side effects in both the disseminated MM model and the plasmacytoma model. Tumor tissue absorbs ACY-1215 with ease. Furthermore, the drug does not build up in tumor tissue, as shown by the simultaneous decrease in acetylated α-tubulin in tumor tissue and blood cells by 24 hours post-dosage. [1]
Enzyme Assay
ACY-1215 is dissolves and is then diluted to six times the final concentration 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). HDAC enzymes are pre-incubated with ACY-1215 for 10 minutes prior to the addition of the substrate, and they are diluted to 1.5 times the final concentration in assay buffer. The Michaelis constant (Km), as ascertained by a titration curve, is equivalent to the quantity of FTS (HDAC1, HDAC2, HDAC3, and HDAC6) or MAZ-1675 (HDAC4, HDAC5, HDAC7, HDAC8, and HDAC9) used for each enzyme. FTS or MAZ-1675 is diluted with 0.3μM sequencing grade trypsin in assay buffer to six times the final concentration. The plate is put into a SpectraMax M5 microtiter plate reader after the substrate/trypsin mix has been added to the enzyme/compound mix and shaken for 60 seconds. Following the peptide substrate's lysine side chain's deacetylation, the enzymatic reaction is watched for the release of 7-amino-4-methoxy-coumarin over a 30-minute period. The reaction's linear rate is then computed.
Cell Assay
Peripheral blood mononuclear cells (PBMCs) with immunoblots from healthy donors are isolated and incubated with increasing doses of ACY-1215 for 48 hours while 2.5 μg/mL phytohemagglutinin (PHA) is present. DNA synthesis is measured using thymidine uptake that has been tritium-tagged. Human blood is used to isolate CD4+T cells using the Rosette Sep negative-selection kit. Cells are stimulated by CD3/CD28 Dynabeads for seven days while the compounds are present. AlamarBlue is a tool for viability analysis of cells. 96-well culture plates containing medium, different concentrations of ACY-1215, bortezomib, and/or recombinant IL-6 (10 ng/mL) or insulin-like growth factor-1 (IGF-1; 50 ng/mL) are used to cultivate MM cells (2-4 × 104 cells/well) for a full day at 37°C. We then verify that tritiated thymidine has been incorporated.
Animal Protocol
Mice: Male SCID mice are inoculated subcutaneously with 5×106 MM.1S cells in 100 μL of serum-free RPMI 1640 medium to assess the in vivo anti-MM activity of Ricolinostat. Mice with detectable tumors are given either intraperitoneally (IP) with Ricolinostat 50 mg/kg dissolved in 10% DMSO in 5% dextrose in water five days a week for three weeks, or intraweekly (IV) with PS-341 0.5 mg/kg dissolved in 0.9% saline solution for three weeks, in combination with the same dosage schedule used for the individual agents. At the same time as the combination group, the control group receives the carrier alone. Tumor volume is computed using the formula V=0.5(a×b2), where a is the tumor's long diameter and b is its short diameter. Tumor size is measured every other day in two dimensions using calipers. Once the tumor is ulcerated or grows to a size of 2 cm3, the mice die. From the first day of treatment until death, survival and tumor growth are assessed.
References

[1]. Blood . 2012 Mar 15;119(11):2579-89.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C24H27N5O3
Molecular Weight
433.5
Exact Mass
433.21
Elemental Analysis
C, 66.50; H, 6.28; N, 16.16; O, 11.07
CAS #
1316214-52-4
Appearance
Pale peach fluffy powder
SMILES
C1=CC=C(C=C1)N(C2=CC=CC=C2)C3=NC=C(C=N3)C(=O)NCCCCCCC(=O)NO
InChi Key
QGZYDVAGYRLSKP-UHFFFAOYSA-N
InChi Code
InChI=1S/C24H27N5O3/c30-22(28-32)15-9-1-2-10-16-25-23(31)19-17-26-24(27-18-19)29(20-11-5-3-6-12-20)21-13-7-4-8-14-21/h3-8,11-14,17-18,32H,1-2,9-10,15-16H2,(H,25,31)(H,28,30)
Chemical Name
N-[7-(hydroxyamino)-7-oxoheptyl]-2-(N-phenylanilino)pyrimidine-5-carboxamide
Synonyms
Ricolinostat; Rocilinostat; ACY 1215; ACY1215; ACY-1215
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
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: 5mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.3068 mL 11.5340 mL 23.0681 mL
5 mM 0.4614 mL 2.3068 mL 4.6136 mL
10 mM 0.2307 mL 1.1534 mL 2.3068 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01997840 Active
Recruiting
Drug: ACY-1215 (Ricolinostat)
in combination with pomalidomide
and dexamethasone
Multiple Myeloma Celgene March 1, 2014 Phase 1
Phase 2
NCT02787369 Active
Recruiting
Drug: ACY-1215
Drug: Ibrutinib
Recurrent Chronic Lymphoid
Leukemia
Dana-Farber Cancer Institute May 2016 Phase 1
NCT01323751 Completed Drug: ACY-1215 Multiple Myeloma Celgene July 2011 Phase 1
Phase 2
NCT02632071 Completed Drug: ACY-1215
Drug: Nab-paclitaxel
Metastatic Breast Cancer
Breast Carcinoma
Columbia University March 1, 2016 Phase 1
NCT01583283 Completed Drug: ACY-1215
Drug: lenalidomide
Multiple Myeloma Celgene July 12, 2012 Phase 1
Biological Data
  • Rocilinostat (ACY-1215)

  • Rocilinostat (ACY-1215)

  • Rocilinostat (ACY-1215)

  • Rocilinostat (ACY-1215)
    ACY-1215 PK/PD profile.Blood.2012 Mar 15;119(11):2579-89.
  • Rocilinostat (ACY-1215)
    ACY-1215 selectively inhibits HDAC6.Blood.2012 Mar 15;119(11):2579-89.
  • Rocilinostat (ACY-1215)
    ACY-1215 in combination with bortezomib induces significant anti-MM activity in vivo.Blood.2012 Mar 15;119(11):2579-89.
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