Discovery of new low-molecular-weight p53–Mdmx disruptors and their anti-cancer activities |
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| Institution: | 1. Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan;2. Department of Neurology, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan;3. Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan;1. Kuban State Technological University, Moskovskaya St. 2, Krasnodar 350072, Russian Federation;2. North-Ossetian State University, Vatutina St. 43-46, Vladikavkaz 362025, Russian Federation;3. Perm State University, Bukireva St. 15, Perm 614990, Russian Federation;1. MRC Centre for Reproductive Health, The Queen''s Medical Research Institute, The University of Edinburgh, Edinburgh, UK;2. Edinburgh Royal Hospital for Sick Children, Edinburgh, UK;3. Department of Pathology, Western General Hospital, Edinburgh, UK;4. Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands;5. Pediatric Urology, Erasmus MC-University Medical Center Rotterdam, Josephine Nefkens Institute, Rotterdam, The Netherlands;6. Department of Urology, Western General Hospital, Edinburgh, UK;1. Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Max-von-Laue Str. 9, D-60439, Frankfurt am Main, Germany;2. Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA;1. College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, China;2. Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN, 46556, United States;3. The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, 361005, China |
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| Abstract: | Although several p53–Mdm2-binding disruptors have been identified to date, few studies have been published on p53–Mdmx-interaction inhibitors. In the present study, we demonstrated that o-aminothiophenol derivatives with molecular weights of 200–300 selectively inhibited the p53–Mdmx interaction. S-2-Isobutyramidophenyl 2-methylpropanethioate (K-178) (1c) activated p53, up-regulated the expression of its downstream genes such as p21 and Mdm2, and preferentially inhibited the growth of cancer cells with wild-type p53 over those with mutant p53. Furthermore, we found that the S-isobutyryl-deprotected forms 1b and 3b of 1c and S-2-benzamidophenyl 2-methylpropanethioate (K-181) (3c) preferentially inhibited the p53–Mdmx interaction over the p53–Mdm2 interaction, respectively, by using a Flag-p53 and glutathione S-transferase (GST)-fused protein complex (Mdm2, Mdmx, DAPK1, or PPID). In addition, the interaction of p53 with Mdmx was lost by replacing a sulfur atom with an oxygen atom in 1b and 1c. These results suggest that sulfides such as 1b, 3b, 4b, and 5b interfere with the binding of p53–Mdmx, resulting in the dissociation of the two proteins. Furthermore, the results of oral administration experiments using xenografts in nude mice indicated that 1c reduced the volume of tumor masses to 49.0% and 36.6% that of the control at 100 mg/kg and 150 mg/kg, respectively, in 40 days. |
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| Keywords: | p53–Mdmx-interaction inhibitor Protein–protein interaction inhibitor Modified ELISA GST–Mdmx |
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