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

Ewa Surmiak, Aleksandra Twarda-Clapa, Krzysztof M. Zak, Bogdan Musielak, Marcin D. Tomala, Katarzyna Kubica, Przemyslaw Grudnik, Mariusz Madej, Mateusz Jablonski, Jan Potempa, Justyna Kalinowska-Tluscik, Alexander Dömling, Grzegorz Dubin, Tad A. Holak

OnderzoeksoutputAcademicpeer review

21 Citaten (Scopus)

Samenvatting

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.
Originele taal-2English
Pagina's (van-tot)3310-3318
Aantal pagina's9
TijdschriftACS chemical biology
Volume11
Nummer van het tijdschrift12
DOI's
StatusPublished - dec-2016
  • CCDC 1054956: Experimental Crystal Structure Determination

    Surmiak, E. (Contributor), Twarda-Clapa, A. (Contributor), Zak, K. M. (Contributor), Musielak, B. (Contributor), Tomala, M. D. (Contributor), Kubica, K. (Contributor), Grudnik, P. (Contributor), Madej, M. (Contributor), Jablonski, M. (Contributor), Potempa, J. (Contributor), Kalinowska-Tluscik, J. (Contributor), Dömling, A. (Contributor), Dubin, G. (Contributor) & Holak, T. A. (Contributor), University of Groningen, 19-mrt-2015

    Dataset

  • CCDC 1054955: Experimental Crystal Structure Determination

    Surmiak, E. (Contributor), Twarda-Clapa, A. (Contributor), Zak, K. M. (Contributor), Musielak, B. (Contributor), Tomala, M. D. (Contributor), Kubica, K. (Contributor), Grudnik, P. (Contributor), Madej, M. (Contributor), Jablonski, M. (Contributor), Potempa, J. (Contributor), Kalinowska-Tluscik, J. (Contributor), Dömling, A. (Contributor), Dubin, G. (Contributor) & Holak, T. A. (Contributor), University of Groningen, 19-mrt-2015

    Dataset

  • CCDC 1054957: Experimental Crystal Structure Determination

    Surmiak, E. (Contributor), Twarda-Clapa, A. (Contributor), Zak, K. M. (Contributor), Musielak, B. (Contributor), Tomala, M. D. (Contributor), Kubica, K. (Contributor), Grudnik, P. (Contributor), Madej, M. (Contributor), Jablonski, M. (Contributor), Potempa, J. (Contributor), Kalinowska-Tluscik, J. (Contributor), Dömling, A. (Contributor), Dubin, G. (Contributor) & Holak, T. A. (Contributor), University of Groningen, 19-mrt-2015

    Dataset

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