Highly Potent Non-Carboxylic Acid Autotaxin Inhibitors Reduce Melanoma Metastasis and Chemotherapeutic Resistance of Breast Cancer Stem Cells

Autotaxin
(ATX, aka. ENPP2) is the main source of the lipid mediator
lysophosphatidic acid (LPA) in biological fluids. This study reports
on inhibitors of ATX derived by lead optimization of the benzene-sulfonamide in silico hit compound 3. The new analogues
provide a comprehensive structure–activity relationship of
the benzene-sulfonamide scaffold that yielded a series of highly potent
ATX inhibitors. The three most potent analogues (3a,
IC50 ∼ 32 nM; 3b, IC50 ∼
9 nM; and 14, IC50 ∼ 35 nM) inhibit
ATX-dependent invasion of A2058 human melanoma cells in vitro. Two of the most potent compounds, 3b and 3f (IC50 ∼ 84 nM), lack inhibitory action on ENPP6
and ENPP7 but possess weak antagonist action specific to the LPA1 G protein-coupled receptor. In particular, compound 3b potently reduced in vitro chemotherapeutic
resistance of 4T1 breast cancer stem-like cells to paclitaxel and
significantly reduced B16 melanoma metastasis in vivo.