Ricolinostat (ACY-1215)

Names

[ Name ]:
Ricolinostat (ACY-1215)

[Synonym ]:
2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide
5-Pyrimidinecarboxamide, 2-(diphenylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-
ACY-1215
Ricolinostat [USAN]
ACY-63
Rocilinostat
ACY1215
2-(Diphenylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-5-pyrimidinecarboxamide
cc-661
Rocilinostat (ACY-1215)
Ricolinostat

Biological Activity

[Description]:

Ricolinostat (ACY-1215) is a potent and selective HDAC6 inhibitor, with an IC50 of 5 nM. ACY-1215 also inhibits HDAC1, HDAC2, and HDAC3 with IC50s of 58, 48, and 51 nM, respectively.

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> HDAC

Signaling Pathways >> Epigenetics >> HDAC

Research Areas >> Cancer

[Target]

HDAC6:4.7 nM (IC50)

HDAC2:48 nM (IC50)

HDAC3:51 nM (IC50)

HDAC1:58 nM (IC50)

HDAC8:100 nM (IC50)

HDAC7:1400 nM (IC50)

HDAC5:5000 nM (IC50)

HDAC4:7000 nM (IC50)

[In Vitro]

Ricolinostat (ACY-1215) has slight activity against HDAC8 (IC50=0.1 μM), and has minimal activity (IC50>1 μM) against HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2. The effect of Ricolinostat (ACY-1215) on multiple myeloma (MM) cell viability is determined with MTT assays using MM cell lines. Exposure of MM cell lines for 48 hours results in dose-dependent decreased viability, with IC50 values ranging from 2-8μM. Ricolinostat (ACY-1215) demonstrates significant activity in the MM Bortezomib-resistant cell line (ANBL-6.BR), demonstrating the ability of Ricolinostat (ACY-1215) to overcome Bortezomib resistance[1].

[In Vivo]

Mice treated with Ricolinostat (ACY-1215), Bortezomib, or Ricolinostat plus Bortezomib show a significant delay in tumor growth (P=0.01, P=0.006, and P<0.0001, respectively). Combined treatment with Ricolinostat and Bortezomib shows significant suppression of tumor growth and significantly prolonged overall survival (OS) compare with the control group (17 days in the control vs 40 days in the combination-treated group, P<0.0001) and the Ricolinostat (ACY-1215)-treated group (22 days in the Bortezomib group vs 40 days in the combination-treated group, P<0.0001). Weight loss in the combination-treated group is between 4% and 12% compare with the same-day control group values during treatment, with complete recovery after the last injection. As is observed in the plasmacytoma model, a significant therapeutic advantage is found by combining Ricolinostat with Bortezomib compare with either agent alone[1].

[Cell Assay]

The effect of Ricolinostat with or without Bortezomib on the viability of MM cell lines, patient MM cells, and PBMCs is assessed by measuring MTT dye absorbance. PBMCs from healthy donors are isolated and stimulated with 2.5 μg/mL of phytohemagglutinin (PHA) for 48 hours in the presence of increasing concentrations of Ricolinostat (ACY-1215). DNA synthesis is measured by tritiated thymidine uptake. CD4+ T cells are purified from human blood with the Rosette Sep negative-selection kit. Cells are stimulated by CD3/CD28 Dynabeads for 7 days in the presence of compounds. Cell viability is assessed using alamarBlue. MM cells (2-3×104 cells/well) are incubated in 96-well culture plates with medium and different concentrations of Ricolinostat (ACY-1215), Bortezomib, and/or recombinant IL-6 (10 ng/mL) or insulin-like growth factor-1 (IGF-1; 50 ng/mL) for 24 hours at 37°C, and tritiated thymidine incorporation is measured[1].

[Animal admin]

Mice[1] To evaluate the in vivo anti-MM activity of Ricolinostat, male SCID mice are inoculated subcutaneously with 5×106 MM.1S cells in 100 μL of serum-free RPMI 1640 medium. When tumors are measurable, mice are treated IP with Ricolinostat 50 mg/kg dissolved in 10% DMSO in 5% dextrose in water consecutively for 5 days a week for 3 weeks; Bortezomib 0.5 mg/kg dissolved in 0.9% saline solution biweekly (IV) for 3 consecutive weeks; or combination with the same dosing regimen used for the individual agents. The control group receive the carrier alone at the same schedule as the combination group. Tumor size is measured every other day in 2 dimensions using calipers, and tumor volume is calculated with the formula: V=0.5(a×b2) where a is the long diameter of the tumor and b is the short diameter of the tumor. Mice are killed when the tumor reaches 2 cm3 or is ulcerated. Survival and tumor growth are evaluated from the first day of treatment until death.

[References]

[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 Mar 15;119(11):2579-89.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.2±0.1 g/cm3

[ Molecular Formula ]:
C₂₄H₂₇N₅O₃

[ Molecular Weight ]:
433.503

[ Exact Mass ]:
433.211395

[ PSA ]:
114.43000

[ LogP ]:
1.41

[ Index of Refraction ]:
1.620

[ Water Solubility ]:
Insuluble (4.3E-3 g/L) (25 ºC)

Safety Information

[ Hazard Codes ]:
Xi

[ HS Code ]:
2933599090

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2933599090

[ Summary ]:
2933599090. other compounds containing a pyrimidine ring (whether or not hydrogenated) or piperazine ring in the structure. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%