ABC294640
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MedKoo CAT#: 205806

CAS#: 915385-81-8 (free base)

Description: ABC294640, also known as Opaganib, is an orally available, aryladamantane compound and selective inhibitor of sphingosine kinase-2 (SK2) with potential antineoplastic activity. Upon administration, ABC294640 competitively binds to and inhibits SK2, thereby preventing the phosphorylation of the pro-apoptotic amino alcohol sphingosine to sphingosine 1-phosphate (S1P), the lipid mediator that is pro-survival and critical for immunomodulation. This may eventually lead to the induction of apoptosis and may result in an inhibition of cell proliferation in cancer cells overexpressing SK2.


Chemical Structure

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ABC294640
CAS# 915385-81-8 (free base)

Theoretical Analysis

MedKoo Cat#: 205806
Name: ABC294640
CAS#: 915385-81-8 (free base)
Chemical Formula: C23H25ClN2O
Exact Mass: 380.16554
Molecular Weight: 380.9104
Elemental Analysis:

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Related CAS #: 1185157-59-8 (HCl)   915385-81-8 (free base)    

Synonym: ABC-294640; ABC294640; ABC 294640; Opaganib

IUPAC/Chemical Name: (1s,3r,5R,7S)-3-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)adamantane-1-carboxamide

InChi Key: CAOTVXGYTWCKQE-BRNYJPRKSA-N

InChi Code: InChI=1S/C23H25ClN2O/c24-20-3-1-19(2-4-20)22-10-17-9-18(11-22)13-23(12-17,15-22)21(27)26-14-16-5-7-25-8-6-16/h1-8,17-18H,9-15H2,(H,26,27)/t17-,18+,22+,23-

SMILES Code: O=C([C@@]12C[C@]3(C4=CC=C(Cl)C=C4)C[C@@](C2)([H])C[C@](C3)([H])C1)NCC5=CC=NC=C5

Appearance: White solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Opaganib (ABC294640) is a selective, competitive sphingosine kinase 2 (SK2) inhibitor with Ki of 9.8 μM.
In vitro activity: An aryladamantane compound, termed ABC294640 [3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide], was identified to selectively inhibit SK2 activity in vitro, acting as a competitive inhibitor with respect to sphingosine with a K(i) of 9.8 muM, and attenuates S1P formation in intact cells. In tissue culture, ABC294640 suppresses the proliferation of a broad panel of tumor cell lines, and inhibits tumor cell migration concomitant with loss of microfilaments. Using recombinant human SK1 and SK2, ABC294640 demonstrated dose-dependent inhibition of SK2 with an IC50 of approximately 60 μM without affecting the activity of SK1 at concentrations up to at least 100 μM (Fig. 2A). Additional studies demonstrated that ABC294640 acts as a competitive inhibitor with respect to sphingosine, making the IC50 strongly affected by the concentration of sphingosine used in the assay. Kinetic analyses of varying concentrations of ABC294640 in the presence of 2.5 to 25 μM sphingosine indicated a Ki of 9.8 ± 1.4 μM for the inhibition of SK2 (Fig. 2B). It was also important to determine the ability of ABC294640 to inhibit endogenous SK activity in an intact cell model. MDA-MB-231 cells were incubated with [3H]sphingosine at a final concentration of 1 μM to test this. In this assay, ABC294640 decreased [3H]S1P formation in a dose-dependent fashion with an IC50 value of 26 μM. The effects of ABC294640 on the proliferation of human tumor cell lines representing major tumor types were determined by use of the sulforhodamine B assay for quantifying cell number. As indicated in Table 2, ABC294640 inhibited tumor cell proliferation with IC50 values ranging from approximately 6 to 48 μM with Hep-G2 and HT-29 cells being the most and least sensitive, respectively. It is notable that the IC50 for inhibition of the proliferation of MDA-MB-231 cells closely matches the IC50 for suppression of SK activity in this cell line, i.e., 29 and 26 μM, respectively, supporting the hypotheses that the antiproliferative effects of ABC294640 are mediated by inhibition of SK activity, and that SK2, in particular, is important for cell proliferation. Reference: J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20061445/
In vivo activity: The antitumor activity of ABC294640 was tested in a syngeneic tumor model that uses the mouse JC mammary adenocarcimona cell line growing subcutaneously in immunocompetent BALB/c mice. Because of the excellent oral absorption, it was determined the ability of orally delivered ABC294640 to reduce tumor growth in vivo. The SK inhibitor was administered to fasted mice on odd days at doses ranging from 3.5 to 100 mg/kg. Body weights and tumor volumes were monitored daily. As demonstrated in Fig. 7, ABC294640 caused dose-dependent reductions in the growth of the mammary adenocarcinoma xenografts. Body weights in each treatment group remained unchanged from vehicle-treated mice during the course of the study (data not shown). Comparison with the potencies in the tumor studies with the toxicity data described above reveals that ABC294640·HCl has a therapeutic index of greater than 7 (250 mg/kg nontoxic dose / 35 mg/kg antitumor activity). Thus, this SK2 inhibitor has an excellent therapeutic index. Reference: J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20061445/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 76.0 199.52
Ethanol 28.0 73.51

Preparing Stock Solutions

The following data is based on the product molecular weight 380.9104 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
In vitro protocol: 1. French KJ, Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V, Upson JJ, Green CL, Keller SN, Smith CD. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. doi: 10.1124/jpet.109.163444. Epub 2010 Jan 8. PMID: 20061445; PMCID: PMC2846016. 2. Beljanski V, Knaak C, Zhuang Y, Smith CD. Combined anticancer effects of sphingosine kinase inhibitors and sorafenib. Invest New Drugs. 2011 Dec;29(6):1132-42. doi: 10.1007/s10637-010-9452-0. Epub 2010 May 18. PMID: 20473784; PMCID: PMC3089696.
In vivo protocol: 1. French KJ, Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V, Upson JJ, Green CL, Keller SN, Smith CD. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. doi: 10.1124/jpet.109.163444. Epub 2010 Jan 8. PMID: 20061445; PMCID: PMC2846016. 2. Beljanski V, Knaak C, Zhuang Y, Smith CD. Combined anticancer effects of sphingosine kinase inhibitors and sorafenib. Invest New Drugs. 2011 Dec;29(6):1132-42. doi: 10.1007/s10637-010-9452-0. Epub 2010 May 18. PMID: 20473784; PMCID: PMC3089696.

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 1: White MD, Chan L, Antoon JW, Beckman BS. Targeting ovarian cancer and chemoresistance through selective inhibition of sphingosine kinase-2 with ABC294640. Anticancer Res. 2013 Sep;33(9):3573-9. PubMed PMID: 24023282.

2: Fitzpatrick LR, Green C, Maines LW, Smith CD. Experimental osteoarthritis in rats is attenuated by ABC294640, a selective inhibitor of sphingosine kinase-2. Pharmacology. 2011;87(3-4):135-43. doi: 10.1159/000323911. Epub 2011 Feb 22. PubMed PMID: 21346391.

3: Beljanski V, Lewis CS, Smith CD. Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. Cancer Biol Ther. 2011 Mar 1;11(5):524-34. Epub 2011 Mar 1. PubMed PMID: 21258214; PubMed Central PMCID: PMC3087901.

4: Antoon JW, White MD, Meacham WD, Slaughter EM, Muir SE, Elliott S, Rhodes LV, Ashe HB, Wiese TE, Smith CD, Burow ME, Beckman BS. Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology. 2010 Nov;151(11):5124-35. doi: 10.1210/en.2010-0420. Epub 2010 Sep 22. PubMed PMID: 20861237; PubMed Central PMCID: PMC2954724.

5: French KJ, Zhuang Y, Maines LW, Gao P, Wang W, Beljanski V, Upson JJ, Green CL, Keller SN, Smith CD. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. doi: 10.1124/jpet.109.163444. Epub 2010 Jan 8. PubMed PMID: 20061445; PubMed Central PMCID: PMC2846016.



Additional Information

ABC294640 selectively inhibits SK2 activity in vitro, acting as a competitive inhibitor with respect to sphingosine with a K(i) of 9.8 muM, and attenuates S1P formation in intact cells. In tissue culture, ABC294640 suppresses the proliferation of a broad panel of tumor cell lines, and inhibits tumor cell migration concomitant with loss of microfilaments. In vivo, ABC294640 has excellent oral bioavailability, and demonstrates a plasma clearance half-time of 4.5 h in mice. Oral administration of ABC294640 to mice bearing mammary adenocarcinoma xenografts results in dose-dependent antitumor activity associated with depletion of S1P levels in the tumors and progressive tumor cell apoptosis. Therefore, this newly developed SK2 inhibitor provides an orally available drug candidate for the treatment of cancer and other diseases.   (source: J Pharmacol Exp Ther. 2010 Apr;333(1):129-39. Epub 2010 Jan 8.)