Opaganib (ABC294640)

Catalog No.S7174

Opaganib (ABC294640) Chemical Structure

Molecular Weight(MW): 380.91

Opaganib (ABC294640) is an orally bioavailable and selective sphingosine kinase-2 (SphK2) inhibitor with IC50 of approximately 60 μM. Phase 1/2.

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Biological Activity

Description Opaganib (ABC294640) is an orally bioavailable and selective sphingosine kinase-2 (SphK2) inhibitor with IC50 of approximately 60 μM. Phase 1/2.
Targets
SphK2 [1]
(Cell-free assay)
60 μM
In vitro

ABC294640 markedly alters the ratio of ceramide/S1P consistent with inhibition of SK activity in MDA-MB-231 cells. ABC294640 inhibits tumor cell proliferation with IC50 values ranging from approximately 6 to 48 μM, and impairs tumor cell migration concomitant with loss of microfilaments. [1] ABC294640 induces nonapoptotic cell death, morphological changes in lysosomes, formation of autophagosomes, and increases in acidic vesicles in A-498, PC-3, and MDA-MB-231 cells. [2] In both MCF-7 and ER-transfected HEK293 cells, ABC294640 decreases E2-stimulated ERE-luciferase activity. [3]

In vivo In mice bearing mammary adenocarcinoma xenografts, ABC294640 (100 mg/kg, p.o.) significantly reduce tumor growth, associated with depletion of S1P levels. [1] In severe combined immunodeficient mice bearing A-498 xenografts, ABC294640 delays tumor growth and elevates autophagy markers. [2] ABC294640 protects against liver transplantation-induced inflammation and cross-talk between innate and adaptive immunities, major events precipitating and exacerbating graft injury, and improves liver function and survival. [4]

Protocol

Kinase Assay:[1]
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Sphingosine Kinase Assays:

The IC50 values for ABC294640 and DMS are determined by a newly developed HPLC-based SK activity assay. In brief, the test compounds are incubated with recombinant SK1 or SK2 and NBD-Sph in the isozyme-selective assay buffers detailed below with 1 mg/ml fatty acid-free bovine serum albumin, 100 μM ATP, and 400 μM MgCl2. The product, i.e., NBD-S1P, is separated from NBD-Sph by HPLC as follows: Waters 2795 HPLC system with a Waters 2495 fluorescence detector, C8 Chromolith RP-8e column (100 × 4.6 mm), 1 ml/min mobile phase (acetonitrile/20 mM sodium phosphate buffer, pH2.5, at 45:55). Fluorescence is monitored with excitation at 465 nm and emission at 531 nm. The ratio of NBD-S1P/(NBD-Sph + NBD-S1P) is used as a measure of SK activity. SK-isozyme selective assay buffers each contained 20 mM Tris, pH7.4, 5 mM EDTA, 5 mM EGTA, 3 mM β-mercaptoethanol, 5% glycerol, 1× protease inhibitors and 1× phosphatase inhibitors. For the SK1 assay buffer, 0.25% (final) Triton X-100 is added; and for the SK2 buffer, 1 M (final) KCl is added. Assays are run for 2 h at room temperature, and then a 1.5 volume of methanol is added to terminate the kinase reaction. After 10 min, the samples are centrifuged at 20,000g to pellet the precipitated protein, and the supernatants are analyzed by HPLC. In experiments to determine the Ki for inhibition of SK2 by ABC294640, the ADP Quest assay system is used to measure kinase activity in the presence of varying concentrations of sphingosine and ABC294640. To determine the effects of ABC294640 on cellular SK activity, near-confluent MDA-MB-231 cells are serum-starved overnight, and then treated with varying concentrations of ABC294640. The cells are then incubated with [3H]sphingosine at a final concentration of 1 μM. The cells take up the exogenous sphingosine, which is converted to S1P via SK activity, and [3H]S1P is separated from [3H]sphingosine by extraction and quantified by scintillation counting.
Cell Research:[1]
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  • Cell lines: 1025LU, Hep-G2, A-498, MCF-7, Caco-2, MDA-MB-231, HT-29, Panc-1, DU145, T24, and SK-OV-3 cell lines
  • Concentrations: ~50 μM
  • Incubation Time: 72 h
  • Method: To determine the effects of the test compounds on proliferation, cells are plated into 96-well microtiter plates and allowed to attach for 24 h. Varying concentrations of ABC294640 are added to individual wells and the cells are incubated for an additional 72 h. At the end of this period, the number of viable cells is determined by use of the sulforhodamine-binding assay. The percentage of cells killed is calculated as the percentage decrease in sulforhodamine-binding compared with control cultures. Regression analyses of inhibition curves are performed by use of GraphPad Prism.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Female BALB/c mice bearing JC tumors
  • Formulation: 0.375% Polysorbate-80 in PBS
  • Dosages: ~100 mg/kg
  • Administration: p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 76 mg/mL warmed (199.52 mM)
Ethanol 28 mg/mL (73.5 mM)
Water Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+30% PEG 300+5% Tween 80+ddH2O
For best results, use promptly after mixing.
5mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 380.91
Formula

C23H25ClN2O

CAS No. 915385-81-8
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT03377179 Recruiting Cholangiocarcinoma|Cholangiocarcinoma Non-resectable|Cholangiocarcinoma Perihilar|Cholangiocarcinoma Extrahepatic|Cholangiocarcinoma Intrahepatic RedHill Biopharma Limited March 7 2018 Phase 2
NCT02229981 Withdrawn Diffuse Large B Cell Lymphoma|Kaposi Sarcoma RedHill Biopharma Limited|Louisiana State University Health Sciences Center in New Orleans|Apogee Biotechnology Corporation July 2014 Phase 1|Phase 2
NCT01488513 Completed Pancreatic Cancer|Unspecified Adult Solid Tumor Protocol Specific RedHill Biopharma Limited|Apogee Biotechnology Corporation|Medical University of South Carolina|FDA Office of Orphan Products Development|National Cancer Institute (NCI) August 2011 Phase 1
NCT02939807 Recruiting Carcinoma Hepatocellular Medical University of South Carolina|National Cancer Institute (NCI)|Apogee Biotechnology Corporation December 14 2016 Phase 2
NCT02757326 Recruiting Multiple Myeloma RedHill Biopharma Limited|Apogee Biotechnology Corporation|Duke University|National Cancer Institute (NCI) December 13 2016 Phase 1|Phase 2

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID