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A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction.
Surmiak, Ewa; Twarda-Clapa, Aleksandra; Zak, Krzysztof M; Musielak, Bogdan; Tomala, Marcin D; Kubica, Katarzyna; Grudnik, Przemyslaw; Madej, Mariusz; Jablonski, Mateusz; Potempa, Jan; Kalinowska-Tluscik, Justyna; Dömling, Alexander; Dubin, Grzegorz; Holak, Tad A.
Afiliación
  • Surmiak E; Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
  • Twarda-Clapa A; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.
  • Zak KM; Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
  • Musielak B; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.
  • Tomala MD; Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
  • Kubica K; Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
  • Grudnik P; Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
  • Madej M; Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
  • Jablonski M; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.
  • Potempa J; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.
  • Kalinowska-Tluscik J; Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
  • Dömling A; Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
  • Dubin G; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.
  • Holak TA; Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
ACS Chem Biol ; 11(12): 3310-3318, 2016 12 16.
Article en En | MEDLINE | ID: mdl-27709883
The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.
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Bases de datos: MEDLINE Asunto principal: Pirroles / 4-Butirolactona / Proteína p53 Supresora de Tumor / Proteínas Proto-Oncogénicas c-mdm2 / Mapas de Interacción de Proteínas Límite: Humans Idioma: En Revista: ACS Chem Biol Año: 2016 Tipo del documento: Article País de afiliación: Polonia
Buscar en Google
Bases de datos: MEDLINE Asunto principal: Pirroles / 4-Butirolactona / Proteína p53 Supresora de Tumor / Proteínas Proto-Oncogénicas c-mdm2 / Mapas de Interacción de Proteínas Límite: Humans Idioma: En Revista: ACS Chem Biol Año: 2016 Tipo del documento: Article País de afiliación: Polonia