Design, Synthesis, and Biological Evaluation of Nedd4 E3 Ubiquitin Ligase Small Molecule Inhibitors

Protein ubiquitination and deubiquitination are closely associated with tumorigenesis. The incidence of most tumorigenesis associated with abnormal expression of oncogenes and tumor suppressor genes. Nedd4 is an E3 ubiquitin ligase and highly expressed in prostate cancer cells, breast cancer cells, and ovarian cancer cells [1]. Based on the three-dimensional structure of Nedd4 ubiquitin ligase and its characteristics, we used computer simulations and structural biology information to design and synthesize compounds to inhibit the activity of Nedd4 ubiquitin ligase. In this paper, we would like to report the design, synthesis, and biological activities of these compounds. Among those compounds, five new compounds have not been reported before. All the newly synthesized compounds were characterized by 1H NMR and were tested for their antitumor activities using DU145, PC3, and PNT1A cell lines. The results showed that 4-(4-chlorobenzoyl) piperazin-1-yl) (4-(phenoxymethyl) phenyl) methanone has antiproliferative activity against DU145 with an IC50 of 3.86 μM.