ABC294640 - CAS 915385-81-8
Catalog number: 915385-81-8
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
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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.
white solid powder
ABC-294640; ABC 294640; 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide.
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Apogee Biotechnology Corporation.
1.Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells.
Ding X1,2, Chaiteerakij R2,3, Moser CD2, Shaleh H2, Boakye J2, Chen G2, Ndzengue A2, Li Y2, Zhou Y2, Huang S2, Sinicrope FA2, Zou X1, Thomas MB4, Smith CD5, Roberts LR2. Oncotarget. 2016 Mar 4. doi: 10.18632/oncotarget.7914. [Epub ahead of print]
Sphingosine kinase 2 (Sphk2) has an oncogenic role in cancer. A recently developed first-in-class Sphk2 specific inhibitor ABC294640 displays antitumor activity in many cancer models. However, the role of Sphk2 and the antitumor activity of its inhibitor ABC294640 are not known in cholangiocarcinoma. We investigated the potential of targeting Sphk2 for the treatment of cholangiocarcinoma. We found that Sphk2 is overexpressed in five established human cholangiocarcinoma cell lines (WITT, HuCCT1, EGI-1, OZ and HuH28) and a new patient-derived cholangiocarcinoma cell line (LIV27) compared to H69 normal cholangiocytes. Inhibition of Sphk2 by ABC294640 inhibited proliferation and induced caspase-dependent apoptosis. Furthermore, we found that ABC294640 inhibited STAT3 phosphorylation, one of the key signaling pathways regulating cholangiocarcinoma cell proliferation and survival. ABC294640 also induced autophagy. Inhibition of autophagy by bafilomycin A1 or chloroquine potentiated ABC294640-induced cytotoxicity and apoptosis.
2.Targeting sphingosine kinase 2 (SphK2) by ABC294640 inhibits colorectal cancer cell growth in vitro and in vivo.
Xun C1,2, Chen MB3, Qi L4, Tie-Ning Z5, Peng X6, Ning L7, Zhi-Xiao C8, Li-Wei W9,10. J Exp Clin Cancer Res. 2015 Sep 4;34:94. doi: 10.1186/s13046-015-0205-y.
BACKGROUND: Colorectal cancer (CRC) is a major health problem in China and around the world. It is one of the leading causes of cancer-related deaths. Research groups are thus searching for novel and more efficient anti-CRC agents.
3.The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo.
Venant H1, Rahmaniyan M2, Jones EE3, Lu P1, Lilly MB4, Garrett-Mayer E5, Drake RR3, Kraveka JM2, Smith CD6, Voelkel-Johnson C7. Mol Cancer Ther. 2015 Dec;14(12):2744-52. doi: 10.1158/1535-7163.MCT-15-0279. Epub 2015 Oct 22.
Despite recent advances in the development of novel therapies against castration-resistant prostate cancer, the advanced form of the disease remains a major treatment challenge. Aberrant sphingolipid signaling through sphingosine kinases and their product, sphingosine-1-phosphate, can promote proliferation, drug resistance, angiogenesis, and inflammation. The sphingosine kinase 2 inhibitor ABC294640 is undergoing clinical testing in cancer patients, and in this study we investigated the effects this first-in-class inhibitor in castration-resistant prostate cancer. In vitro, ABC294640 decreased prostate cancer cell viability as well as the expression of c-Myc and the androgen receptor, while lysosomal acidification increased. ABC294640 also induced a greater than 3-fold increase in dihydroceramides that inversely correlated with inhibition of dihydroceramide desaturase (DEGS) activity. Expression of sphingosine kinase 2 was dispensable for the ABC294640-mediated increase in dihydroceramides.
4.Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells.
McNaughton M1, Pitman M2, Pitson SM2, Pyne NJ1, Pyne S1. Oncotarget. 2016 Feb 25. doi: 10.18632/oncotarget.7693. [Epub ahead of print]
Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells.
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CAS 915385-81-8 ABC294640

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