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Antitumor Activity of a Novel Sphingosine-1-Phosphate 2 Antagonist, AB1, in Neuroblastoma

The Journal of Pharmacology and Experimental Therapeutics, ISSN: 0022-3565, Vol: 354, Issue: 3, Page: 261-268
2015
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Article Description

The bioactive lipid sphingosine-1-phosphate (S1P) and its receptors (S1P 1–5 ) play critical roles in many pathologic processes, including cancer. The S1P axis has become a bona fide therapeutic target in cancer. JTE-013 [ N -​(2,​6-​dichloro-​4-​pyridinyl)-​2-​[1,​3-​dimethyl-​4-​(1-​methylethyl)-​1 H -​pyrazolo[3,​4-​ b ]pyridin-​6-​yl]-​hydrazinecarboxamide], a known S1P 2 antagonist, suffers from instability in vivo. Structurally modified, more potent, and stable S1P 2 inhibitors would be desirable pharmacological tools. One of the JTE-013 derivatives, AB1 [ N -(1 H -4-isopropyl-1-allyl-3-methylpyrazolo[3,4- b ]pyridine-6-yl)-amino- N ′-(2,6-dichloropyridine-4-yl) urea], exhibited improved S1P 2 antagonism compared with JTE-013. Intravenous pharmacokinetics indicated enhanced stability or slower clearance of AB1 in vivo. Migration assays in glioblastoma showed that AB1 was slightly more effective than JTE-013 in blocking S1P 2 -mediated inhibition of cell migration. Functional studies in the neuroblastoma (NB) cell line SK-N-AS showed that AB1 displayed potency at least equivalent to JTE-013 in affecting signaling molecules downstream of S1P 2. Similarly, AB1 inhibition of the growth of SK-N-AS tumor xenografts was improved compared with JTE-013. Cell viability assays excluded that this enhanced AB1 effect is caused by inhibition of cancer cell survival. Both JTE-013 and AB1 trended to inhibit (C-C motif) ligand 2 expression and were able to significantly inhibit subsequent tumor-associated macrophage infiltration in NB xenografts. Interestingly, AB1 was more effective than JTE-013 in inhibiting the expression of the profibrotic mediator connective tissue growth factor. The terminal deoxynucleotidyl transferase–mediated digoxigenin-deoxyuridine nick-end labeling assay and cleaved caspase-3 detection further demonstrated that apoptosis was increased in AB1-treated NB xenografts compared with JTE-013. Overall, the modification of JTE-013 to produce the AB1 compound improved potency, intravenous pharmacokinetics, cellular activity, and antitumor activity in NB and may have enhanced clinical and experimental applicability.

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