Discovery of new low-molecular-weight p53–Mdmx disruptors and their anti-cancer activities. Issue 8 (15th April 2016)

• Record Type: Journal Article
• Authors: Uesato, Shinichi; Matsuura, Yoshihiro; Matsue, Saki; Sumiyoshi, Takaaki; Hirata, Yoshiyuki; Takemoto, Suzuho; Kawaratani, Yasuyuki; Yamai, Yusuke; Ishida, Kyoji; Sasaki, Tsutomu; Enari, Masato
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 8(2016)
• Page Start: 1919
• Page End: 1926
• Publication Date: 2016-04-15
• Subjects: o-Aminothiophenol derivative -- p53–Mdmx-interaction inhibitor -- Protein–protein interaction inhibitor -- Modified ELISA -- GST–Mdmx; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.03.021
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 forms1b and3b of1c 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 in1b and1c . These results suggest that sulfides such as1b, 3b, 4b, and5b 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 that1c 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.