Discovery of dual tubulin-NEDDylation inhibitors with antiproliferative activity

Abstract

Although various dual-target tubulin inhibitors have been designed and synthesised, no dual tubulin-NEDDylation inhibitors as antiproliferative agents were reported so far. In this work, a series of trimethoxyphenyl analogues as potential dual tubulin-NEDDylation inhibitors were synthesised and evaluated for their antiproliferative activity. Among them, compound C11 exhibited the most potent inhibitory activity with IC₅₀ values of 1.17, 2.48, and 1.47 μM against HepG2, PC3, and MCF7 cells, respectively. In addition, it displayed the potent inhibitory activity against tubulin with an IC₅₀ value of 2.40 μM and obviously inhibited tubulin polymerisation in HepG2 cells. Furthermore, C11 inhibited NEDDylation by a ATP-dependent manner. Molecular docking studies revealed that the methoxy group and dithiocarbamate group of C11 could form hydrogen bonds with residues of tubulin and E1 NEDD8-activating enzyme (NAE). These results suggested that compound C11 was a dual tubulin-NEDDylation inhibitor with antiproliferative activity.

Graphical Abstract

Keywords:

• Tubulin
• NEDDylation
• molecular docking
• antiproliferative activity

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by “the Fundamental Research Funds for the Central Universities” [2022-JYB-XJSJJ025].