Structure guided design of potent indole-based ATX inhibitors bearing hydrazone moiety with tumor suppression effects

ATX was capable of catalyzing the hydrolysis of LPC to the lipid mediator LPA which attracted considerable attention on the development of potent ATX inhibitors. Herein, driven by the HTS product indole-based lead 1, a hybridization strategy was utilized to construct the trifluoroacetyl hydrazone moiety through assembling the phenyl thiazole fragment to the indole skeleton of lead 1. After a systematic structure guided optimization, by cycling the phenyl thiazole to the compacted benzothiazole or decreasing the lipophilicity, two promising ATX inhibitors (9j and 25a) were identified with IC50 values of 2.1 nM and 19.0 nM, respectively. All compounds were tested a panel of cancer cell lines and a preliminary affinity on breast cancer cell lines (SI > 16.5) were observed which shed a light on their potential application of breast cancer relevant cases. Through a dedicated docking study, the intramolecular pseudo-ring within the trifluoroacetylhydrazone moiety played a significant role in constraining the binding poses of 9j and 25a. Finally, a binding free energy calculation was conducted to examine the contribution of different interactions in binding affinity. [Display omitted] •Indole analogs bearing trifluoroacetyl hydrazone as potent allosteric ATX inhibitors.•Structure based design was used which furnished 9j (2.1 nM) and 25a (19.0 nM).•9j &25a presented a selectivity profiles on breast cancer cells over other cells.•The intramolecular H-bond in 9j &25a contributes a lot to the binding with ATX.