Abstract
Abstract
Autotaxin is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. Autotaxin is a unique ectonucleotide pyrophosphatase and phosphodiesterase that facilitates the removal of a choline headgroup from lysophosphatidylcholine to yield lysophosphatidic acid, which is a potent lipid stimulator of tumorigenesis. Thus, autotaxin has received renewed attention because it has a prominent role in malignant progression and represents a promising area of research with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Our goal was to discover agents with therapeutic efficacy in melanoma. For this purpose, we synthesized a set of lysophosphatidylcholine analogs that function as irreversible inhibitors of autotaxin and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 – 0.39 μM, consistent with a Ki of 3.50 μM for inhibition of autotaxin by the analog CVS-16 (10b). A control compound, GWJ-A-10, which is missing the critical moiety, had little effect on cell viability and did not inhibit autotaxin. In addition, CVS-16 (10b) significantly inhibited melanoma cell wound closure and pore migration (data not presented herein). Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent autotaxin inhibitor with significant biological activity, both in vitro and in vivo.
Citation Format: Mandi Murph, Guowei Jiang, Molly Altman, Jia Wei, Sterling Tran, Duy Nguyen, Ali Alshamrani, William Hardman, Jianxing Zhang, Glenn Prestwich. Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B35.