Design, synthesis, and biological evaluation of novel HuR inhibitors.

A series of novel HuR inhibitors were designed and synthesized. Evaluation of HuR binding affinity and antitumor activity against MDA-MB-231 cells demonstrated that most compounds exhibited potent HuR engagement and pronounced antitumor effects. Notably, compound 7a displayed a Kᵢ of 0.098 μM for HuR binding and an IC50 of 1.33 μM against MDA-MB-231 cells, representing several-fold improvements over the positive control KH-39. Mechanistically, 7a induces cancer cell apoptosis by reducing the expression levels of prosurvival proteins encoded by HuR target mRNAs, including XIAP, Bcl-2, and Survivin, without altering HuR protein abundance. Molecular docking and molecular dynamics simulations of 7a, 7b, 7c in complex with HuR identified key hydrophobic interactions with residues I113, Y26, and Y63, an ionic interaction with R131, and a hydrogen bond with R97; additionally, 7a formed two supplementary hydrogen bonds with N25 and Y26. Simulations further indicated that hydrophobic interactions constitute the dominant driving force for binding. Collectively, these results highlight compound 7a as a promising HuR-targeted lead for anticancer development.