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ANTITUMOR ACTIVITY OF A NOVEL S1P2 ANTAGONIST AB1
Mei-Hong Li, PhD1, Rolf Swenson, PhD2, Sampa Jana, PhD3, Erik Stolarzewicz, PhD4, Timothy Hla, PhD5, Linda Shapiro, PhD1, Fernando Ferrer, MD6.
1University of Connecticut Health Center, Farmington, CT, USA, 2Arroyo Biosciences LLC, Princeton, NJ, USA, 3TCG Life Sciences Limited, Hinjewadi, Pune, India, 4Chem-Master International Inc., Stony Brook, NY, USA, 5Weill Medical College of Cornell University, New York, NY, USA, 6Connecticut Children's Medical Center/ University of Connecticut Health Center, Hartford/ Farmington, CT, USA.
Introduction: The bioactive lipid sphingosine-1-phosphate (S1P) and its receptors (S1P1-5) play critical roles in many pathological processes including cancer. The S1P axis is becoming a potential therapeutic target. JTE-013 is a literature standard S1P2 antagonist with potential instability in vivo. Through its structure modification, we try to develop more specific and more stable JTE-013 analogs.
Materials & Methods: FLIPR assay was conducted to assess the agonism/antagonism of JTE-013 analogs against S1P1-5. Pharmacokinetic analysis was performed to detect their blood concentrations in mice over different time. Migration assay in glioblastoma (GB) and neuroblastoma (NB) xenograft model were utilized to compare the biological efficacy between JTE-013 and its analogs. Western blot and real-time PCR were performed to compare their efficacy on modulating the expression of S1P2 downstream molecules such as p-Akt, p-ERK, VEGF and CTGF.
Results: One of the JTE-013 analogs, AB1, exhibited better S1P2 antagonism effect compared to JTE-013, with an IC50 of 3.5 nM versus 11 nM of JTE-013. Intravenous pharmacokinetics showed that the blood concentration of AB1 in mice remained higher than that of JTE-013 over 12 hours, indicating better stability or slower clearance of AB1 in vivo. Migration assay in GB showed that AB1 was more potent than JTE-013 to either reverse S1P-mediated cell migration inhibition in S1P2-predominant U118 cells or further enhance S1P-stimulated cell migration in S1P1-predominant U87 cells. In a NB cell line SK-N-AS, AB1 displayed at least the same potency as JTE-013, in reversing S1P-mediated p-Akt inhibition and inhibiting S1P-mediated p-ERK activation, and in inhibiting S1P-induced VEGF and CTGF expression. Further, in SK-N-AS cell-based xenograft tumor model, AB1 displayed stronger tumor inhibition effect compared to that of JTE-013.
Conclusions: AB1 has improved potency and intravenous pharmacokinetics, better cellular activity, and displays stronger anti-tumor activity compared to JTE-013 in NB, and may have enhanced clinical applicability.
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