Abstract 2672: Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma

Abstract

Abstract Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression and represents a promising area of research with significant translational potential. Since ATX inhibitors may have broad implications for therapy, we sought to create a novel series of inhibitors for use against cancer, especially melanoma. Herein we report on the synthesis and biological activity of a targeted affinity label for the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of vinyl sulfone analogs of ATX that function as irreversible inhibitors of ATX and inactivate the enzyme. We commenced biological testing of this compound with viability assays against multiple cancer cell lines whereby the IC50 values ranged from 6.74 - 0.39 μM, which was consistent with the Ki of the vinyl sulfone (3.50 μM). In addition, this compound was also able to significantly inhibit melanoma cell wound closure and pore migration. Most importantly, the vinyl sulfone significantly inhibited melanoma progression using an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that the vinyl sulfone is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo. Note: This abstract was not presented at the meeting. Citation Format: Mandi M. Murph, Molly Altman, Wei Jia, Duy Nguyen, Jada Fambrough, William J. Hardman, Guowei Jiang, Damian Madan, Jianxing Zhang, Glenn D. Prestwich. Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2672. doi:10.1158/1538-7445.AM2014-2672