title: Discovery of new low-molecular-weight p53-Mdmx disruptors and their anti-cancer activities.
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.
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan. Electronic address: suesato@gaia.eonet.ne.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Uesato
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Matsue
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Sumiyoshi
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
authors.forename: Suzuho
authors.initials: S
authors.lastname: Takemoto
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kawaratani
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamai
authors.affiliation: Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ishida
authors.affiliation: Department of Neurology, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita, Osaka 565-0871, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Division of Refractory and Advanced Cancer, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: menari@ncc.go.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Enari
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D008970:Molecular Weight; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C005464:2-aminothiophenol
keywords: GST–Mdmx; Modified ELISA; Protein–protein interaction inhibitor; o-Aminothiophenol derivative; p53–Mdmx-interaction inhibitor