Abstract 5680: Identification and characterization of a novel class of ATX inhibitors.

The lysophospholipase D (autotaxin, ATX) plays an important role in cancer invasion and metastasis. A High-throughput screen of over 10,000 compounds from the University of Cincinnati Drug Discovery Center, identified several small-molecule inhibitors with IC50 values ranging from nanomolar to low micromolar. The pharmacology of the two most potent compounds, 966791(1) and 918103(2), were further characterized in enzyme, cellular, and whole animal systems. Both of these compounds, significantly reduced cell invasion in melanoma cancer cell lines without any apparent cytotoxicity. Compound (1) was shown to be a competitive inhibitor of ATX for both FS-3 and Pnp-TMP substrates, while compound (2) was competitive only for FS-3. This suggest that compound (2) targets the hydrophobic pocket not the active site of ATX, which was supported by docking of compounds 1 and 2, along with mutagenesis data. The potency of the compounds was comparable to each other in each of the assays. Current ATX inhibitors reported in literature target the active site in the catalytic domain. In our search for ATX inhibitors we identified compounds able to inhibit both the active site and hydrophobic pocket. We conclude that these data suggest compounds solely inhibiting the hydrophobic pocket are sufficient to disrupt the ATX-LPA signaling axis can serve as specific small-molecule modulators for mechanistic studies of ATX as well as a potential leads for the development of anti-cancer drugs. Citation Format: James Fells, Sue Chin Lee, Derek Norman, Yuko Fujiwara, Ryoko Tsukahara, Jianxiong Liu, Jason Kirby, Sandra Nelson, Gabor Tigyi. Identification and characterization of a novel class of ATX inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5680. doi:10.1158/1538-7445.AM2013-5680