The rational discovery of multipurpose inhibitors of the ornithine decarboxylase.

Autor: Chai X; National '111' Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, China.; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, The People's Hospital of China Three Gorges University, Yichang, China.; Hubei Key Laboratory of Industrial Microbiology, Institute of Biomedical and Pharmaceutical Sciences, Hubei University of Technology, Wuhan, China., Zhan J; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, The People's Hospital of China Three Gorges University, Yichang, China.; Department of Gynecology and Obstetrics, The First People's Hospital of Yichang, Yichang, China., Pan J; National '111' Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, China.; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, The People's Hospital of China Three Gorges University, Yichang, China., He M; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, The People's Hospital of China Three Gorges University, Yichang, China., Li B; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, The People's Hospital of China Three Gorges University, Yichang, China., Wang J; National '111' Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, China.; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, The People's Hospital of China Three Gorges University, Yichang, China., Ma H; National '111' Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, China.; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, The People's Hospital of China Three Gorges University, Yichang, China., Wang Y; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, The People's Hospital of China Three Gorges University, Yichang, China., Liu S; National '111' Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Industrial Fermentation (Ministry of Education), Hubei University of Technology, Wuhan, China.; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, The People's Hospital of China Three Gorges University, Yichang, China.; Hubei Key Laboratory of Industrial Microbiology, Institute of Biomedical and Pharmaceutical Sciences, Hubei University of Technology, Wuhan, China.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2020 Sep; Vol. 34 (9), pp. 10907-12921. Date of Electronic Publication: 2020 Aug 07.
DOI: 10.1096/fj.202001222R
Abstrakt: Metabolic reprograming is a hallmark of cancer, and the polyamine metabolic network is dysregulated in many cancers. Ornithine decarboxylase (ODC) is a rate-limiting enzyme for polyamine synthesis in the polyamine metabolic network. In many cancer cells, ODC is over-expressed, so this enzyme has been an attracting anti-cancer drug target. In the catalysis axis (pathway), ODC converts ornithine to putrescine. Meanwhile, ODC's activity is regulated by protein-protein interactions (PPIs), including the ODC-OAZ1-AZIN1 PPI axis and its monomer-dimer equilibrium. Previous studies showed that when ODC's activity is inhibited, the PPIs might counteract the inhibition efficiency. Therefore, we proposed that multipurpose inhibitors that can simultaneously inhibit ODC's activity and perturb the PPIs would be very valuable as drug candidates and molecular tools. To discover multipurpose ODC inhibitors, we established a computational pipeline by combining positive screening and negative screening. We used this pipeline for the forward screening of multipurpose ligands that might inhibit ODC's activity, block ODC-OAZ1 interaction and enhance ODC non-functional dimerization. With a combination of different experimental assays, we identified three multipurpose ODC inhibitors. At last, we showed that one of these inhibitors is a promising drug candidate. This work demonstrated that our computational pipeline is useful for discovering multipurpose ODC inhibitors, and multipurpose inhibitors would be very valuable. Similar with ODC, there are a lot of proteins in human proteome that act as both enzymes and PPI components. Therefore, this work is not only presenting new molecular tools for polyamine study, but also providing potential insights and protocols for discovering multipurpose inhibitors to target more important protein targets.
(© 2020 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
Externí odkaz: