ABC294640Sphingosine kinase 2 inhibitor,selective and competitive CAS# 915385-81-8 |
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Quality Control & MSDS
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| Cas No. | 915385-81-8 | SDF | Download SDF |
| PubChem ID | 15604015 | Appearance | Powder |
| Formula | C23H25ClN2O | M.Wt | 380.91 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : 100 mg/mL (262.53 mM; Need ultrasonic) | ||
| Chemical Name | 3-(4-chlorophenyl)-N-(pyridin-4-ylmethyl)adamantane-1-carboxamide | ||
| SMILES | C1C2CC3(CC1CC(C2)(C3)C(=O)NCC4=CC=NC=C4)C5=CC=C(C=C5)Cl | ||
| Standard InChIKey | CAOTVXGYTWCKQE-UHFFFAOYSA-N | ||
| Standard InChI | 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) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | ABC294640 is a selective, competitive sphingosine kinase 2 (SK2) inhibitor with Ki of 9.8 μM.In Vitro:Using recombinant human SK1 and SK2, ABC294640 demonstrates 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. In contrast, N,N-dimethylsphingosine (DMS) inhibits both SK1 and SK2 with IC50 values of approximately 60 and 20 μM, respectively. 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. ABC294640 decreases [3H]S1P formation in a dose-dependent fashion with an IC50 value of 26 μM[1]. IC50 values for ABC294640 are approximately 50 and 60 μM for A-498 and Bxpc-3 cells, respectively; whereas the IC50 values for ABC294735 are approximately 20 and 40 μM for these cells[2].In Vivo:ABC294640 induces a transient minor decrease in the hematocrit of rats. Hematology studies indicate decreases in red blood cell number and hematocrit of approximately 20% in animals given either 100 or 250 mg/kg/day; and a slight increase in neutrophils and decrease in basophils in the treated rats[1]. Mice are gavaged with ABC294640 (50 mg/kg), a selective inhibitor of sphingosine kinase-2 (SK2), 1 h before surgery and subjected to 1 h-warm ischemia to ~70% of the liver followed by reperfusion. ABC294640-treatment largely prevented the increase of sphingosine-1-phosphate (S1P) after ischemia-reperfusion (IR) in vivo[2]. References: | |||||
ABC294640 Dilution Calculator
ABC294640 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.6253 mL | 13.1265 mL | 26.2529 mL | 52.5058 mL | 65.6323 mL |
| 5 mM | 0.5251 mL | 2.6253 mL | 5.2506 mL | 10.5012 mL | 13.1265 mL |
| 10 mM | 0.2625 mL | 1.3126 mL | 2.6253 mL | 5.2506 mL | 6.5632 mL |
| 50 mM | 0.0525 mL | 0.2625 mL | 0.5251 mL | 1.0501 mL | 1.3126 mL |
| 100 mM | 0.0263 mL | 0.1313 mL | 0.2625 mL | 0.5251 mL | 0.6563 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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ABC294640 is a selective and competitive inhibitor of sphingosine kinase 2 (SK2) with IC50 value of 60μM [1].
ABC294640 is a competitive inhibitor of SK2. It shows IC50 value of about 60μM against recombinant human SK2. In the kinetic assay, ABC294640 competes with sphingosine and exerts a Ki value of 9.8μM. Because of its targeting of the sphingosine binding site of SK2, ABC294640 shows no inhibition activity against other 20 kinases. In MDA-MB-231 cells, ABC294640 prevents S1P production with IC50 value of 26μM. Moreover, ABC294640 has anti-proliferation and anti-migration efficacies in tumor cells. It suppresses cell proliferation of a variety of tumor cell lines such as 1025LU, A-498, Caco-2 and HT-29. The IC50 values are ranged from 6μM to 48μM. Furthermore, administration of ABC294640 inhibits tumor growth in the immunocompetent BALB/c mice bearing mammary adenocarcimona xenografts. Besides that, ABC294640 is also found to have greater anti-proliferation effects in ER-positive than ER-negative breast cancer cells. The effect of E2 signaling caused by ABC294640 is expected to be a therapeutic in endocrine-related diseases [1, 2].
References:
[1] French K J, Zhuang Y, Maines L W, et al. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. Journal of Pharmacology and Experimental Therapeutics, 2010, 333(1): 129-139.
[2] Antoon J W, White M D, Meacham W D, et al. Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology, 2010, 151(11): 5124-5135.
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Inhibition of ceramide glucosylation sensitizes lung cancer cells to ABC294640, a first-in-class small molecule SphK2 inhibitor.[Pubmed:27221045]
Biochem Biophys Res Commun. 2016 Aug 5;476(4):230-236.
Sphingosine kinase 2 (SphK2) is proposed as a novel oncotarget for lung cancer. Here, we studied the anti-lung cancer cell activity by ABC294640, a first-in-class SphK2 inhibitor. We showed that ABC294640 suppressed growth of primary and A549 human lung cancer cells, but sparing SphK2-low lung epithelial cells. Inhibition of SphK2 by ABC294640 increased ceramide accumulation, but decreased pro-survival sphingosine-1-phosphate (S1P) content, leading to lung cancer cell apoptosis activation. Significantly, we show that glucosylceramide synthase (GCS) might be a major resistance factor of ABC294640. The GCS inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or GCS shRNA/siRNA knockdown facilitated ABC294640-induced ceramide production and lung cancer cell apoptosis. Reversely, forced overexpression of GCS reduced ABC294640's sensitivity, resulting in decreased ceramide accumulation and apoptosis induction in A549 cells. These findings provide further evidences to support that targeting SphK2 by ABC294640 may be a rational treatment option for lung cancer. Ceramide glucosylation inhibition may further sensitize lung cancer cells to ABC294640.
Suppression of c-Myc and RRM2 expression in pancreatic cancer cells by the sphingosine kinase-2 inhibitor ABC294640.[Pubmed:27517489]
Oncotarget. 2016 Sep 13;7(37):60181-60192.
Pancreatic cancer remains extremely difficult to treat, with the average lifespan following diagnosis being only 3-6 months, resulting in a death to incidence ratio of 0.94. A major reason for this high mortality rate is resistance to the main chemotherapeutic agent used to treat this disease, gemcitabine. Alterations in nucleoside and gemcitabine metabolism, specifically over-expression of ribonucleotide reductase, have been implicated as a major mechanism of resistance to this drug. Here, we show that inhibition of sphingosine kinase-2 by the specific inhibitor ABC294640 is synergistically cytotoxic with gemcitabine toward three human pancreatic cancer cell lines. Treatment with ABC294640 results in decreased expression of both RRM2 and MYC in all three cell lines. Additionally, expression of c-Myc protein and phosphorylation of Rb at S780 both decrease in a dose-dependent manner in response to ABC294640, while acetylation of H3-K9 and p21 levels increase. Pretreatment with the protein phosphatase 1 inhibitor okadaic acid or the ceramide synthase inhibitor fumonisin B1 fails to prevent the effects of ABC294640 on Rb phosphorylation. These data indicate a role for sphingosine kinase-2 in E2F and c-Myc mediated transcription through alteration of histone acetylation and p21 expression. These effects of ABC294640 suggest that it may be an effective agent for pancreatic cancer, particularly in combination with gemcitabine.
Antitumor effect of the novel sphingosine kinase 2 inhibitor ABC294640 is enhanced by inhibition of autophagy and by sorafenib in human cholangiocarcinoma cells.[Pubmed:26956050]
Oncotarget. 2016 Apr 12;7(15):20080-92.
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. In addition, ABC294640 in combination with sorafenib synergistically inhibited cell proliferation of cholangiocarcinoma cells. Strong decreases in STAT3 phosphorylation were observed in WITT and HuCCT1 cells exposed to the ABC294640 and sorafenib combination. These findings provide novel evidence that Sphk2 may be a rational therapeutic target in cholangiocarcinoma. Combinations of ABC294640 with sorafenib and/or autophagy inhibitors may provide novel strategies for the treatment of cholangiocarcinoma.
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.[Pubmed:26934645]
Oncotarget. 2016 Mar 29;7(13):16663-75.
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. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest.
