Background: Autotaxin-LPA signaling has been implicated in cancer progression, and targeted for
the discovery of cancer therapeutic agents.
Objective: Potential ATX inhibitors were synthesized to develop novel leading compounds and effective anticancer
Methods: The present work designs and synthesizes a series of 2,7-subsitituted carbazole derivatives with different
terminal groups R [R = -Cl (I), -COOH (II), -B(OH)2 (III), or -PO(OH)2 (I-IV)]. The inhibition of these
compounds on the enzymatic activity of ATX was measured using FS-3 and Bis-pNpp as substrates, and the
cytotoxicity of these compounds was evaluated using SW620, SW480, PANC-1, and SKOV-3 human carcinoma
cells. Furthermore, the binding of leading compound with ATX was analyzed by molecular docking.
Results: Compound III was shown to be a promising antitumor candidate by demonstrating both good inhibition
of ATX enzymatic activity and high cytotoxicity against human cancer cell lines. Molecular docking study
shows that compound III is located in a pocket, which mainly comprises amino acids 209 to 316 in domain 2 of
ATX, and binds with these residues of ATX through van der Waals, conventional hydrogen bonds, and hydrophobic
Conclusion: Compound III with the terminal group R = -B(OH)2 has the most potent inhibitory effect with the
greatest cytotoxicity to cancer cells. Moreover, the docking model provides a structural basis for the future optimization
of promising antitumor compounds.