CAS#: 915385-81-8

Description: ABC294640 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. (last updated: 1/7/2016).

Synonym: ABC-294640; ABC294640; ABC 294640.

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

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

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.)


 

REFERENCES

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.