2. Academic Validation
  3. A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction

A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction

  • ACS Chem Biol. 2016 Dec 16;11(12):3310-3318. doi: 10.1021/acschembio.6b00596.
Ewa Surmiak 1,  Aleksandra Twarda-Clapa 2 3,  Krzysztof M Zak 2 3,  Bogdan Musielak 1,  Marcin D Tomala 1,  Katarzyna Kubica 1,  Przemyslaw Grudnik 2,  Mariusz Madej 2 3,  Mateusz Jablonski 1,  Jan Potempa 2 3,  Justyna Kalinowska-Tluscik 1,  Alexander Dömling 4,  Grzegorz Dubin 2 3,  Tad A Holak 1 3
Affiliations

Affiliations

  • 1 Faculty of Chemistry, Jagiellonian University , Ingardena 3, 30-060 Krakow, Poland.
  • 2 Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland.
  • 3 Malopolska Centre of Biotechnology, Jagiellonian University , Gronostajowa 7a, 30-387 Krakow, Poland.
  • 4 Faculty of Mathematics and Natural Sciences, Department of Pharmacy, University of Groningen , 9713AV Groningen, The Netherlands.
PMID: 27709883 DOI: 10.1021/acschembio.6b00596
Abstract

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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