Identification of New Putative Autotaxin Inhibitors via Structure-Based Virtual Screening and Evaluation of Their...

Autotaxin (ATX), a lysophospholipase D playing an important role in several inflammatory diseases, as well as in tumor invasion, progression, and metastasis, is an attractive therapeutic target. Herein, we report a virtual screening study of an in-house molecular database. In silico simulations highlighted five putative ATX inhibitors. The enzyme assay showed that compound 3 achieves inhibition potency in the submicromolar range (IC₅₀ = 0.534 µM), whereas all the other test compounds proved to be moderate (2) or weak (1, 4, and 5) inhibitors of ATX at 10 µM concentration. These compounds, evaluated for the in vitro antiproliferative activity in four ATX-expressing cancer cell lines, namely the ovarian cancer cell lines A2780 and SK-OV-3, the breast cancer cells MCF-7, and immortalized mouse embryonic fibroblast cell line NIH/3T3, demonstrated preliminary phenotypic effects, inhibiting cell proliferation with IC₅₀ values mostly in the low micromolar range. Compound 4 (IC₅₀ = 11.5 µM against SK-OV-3) significantly reduced the motility of SK-OV-3 ovarian carcinoma cells in the wound-healing assay, suggesting that it may represent a hit structure for the development of potential antimetastatic agents.