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
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Design, Synthesis, and Biological Evaluation of Nedd4 E3 Ubiquitin Ligase Small Molecule Inhibitors Xiaoli Fu, Jie Chu, Yuyin Li, Shasha Wang, Jie Zhou, Yujie Dai and Aipo Diao
Abstract 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-(4chlorobenzoyl) piperazin-1-yl) (4-(phenoxymethyl) phenyl) methanone has antiproliferative activity against DU145 with an IC50 of 3.86 lM. Keywords Nedd4 ubiquitin ligase
Antitumor DU145 cancer cell Inhibitor
195.1 Introduction Ubiquitination is a way of common protein modification, which is catalyzed by a series of ubiquitination enzymes (E1, E2, E3 ubiquitin ligase) [1]. During the ubiquitination, evolutionary conserved 76 amino acid peptide chain that will be connected to the target protein substrates, to regulate the transport and degradation of the protein, as well as a variety of metabolic pathways in cells [2, 3]. The X. Fu J. Chu Y. Li S. Wang J. Zhou Y. Dai A. Diao (&) College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, People’s Republic of China e-mail: [email protected]
T.-C. Zhang et al. (eds.), Proceedings of the 2012 International Conference on Applied Biotechnology (ICAB 2012), Lecture Notes in Electrical Engineering 251, DOI: 10.1007/978-3-642-37925-3_195, Ó Springer-Verlag Berlin Heidelberg 2014
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abnormal regulation of ubiquitin ligase is closely related to growth of tumors. Small molecule inhibitors of ubiquitin ligase enzyme may provide a theoretical basis for a new target for the prevention and treatment of breast cancer, ovarian cancer, inflammation, neurodegenerative diseases, and other diseases. E3 ubiquitin ligase has substrate specificity of enzymatic properties. Therefore, Nedd4 could be a new target for treatment for cancer. Nedd4 belongs to the HECT E3 ubiquitin ligases family, which includes about 50 members. Nedd4 contains a C-terminal-specific the HECT catalytic structure and a C2 phospholipid-binding structure in the N-terminal domain. The WW domain of the Nedd4 protein comprises of a module with two highly conserved tryptophan residues, which bind to the target proteins that contain a PY motif, e.g.,
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