Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction

Constantinos G. Neochoritis, Jack Atmaj, Aleksandra Twarda-Clapa, Ewa Surmiak, Lukasz Skalniak, Lisa-Maria Köhler, Damian Muszak, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Barbara Beck, Tad A Holak, Alexander Dömling

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Abstract

Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient α-helical N-terminal ''lid'' segment of MDM2 from the proximity of the p53-complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds.

Original languageEnglish
Article number111588
Number of pages35
JournalEuropean Journal of Medicinal Chemistry
Volume182
Early online date6-Aug-2019
DOIs
Publication statusPublished - 15-Nov-2019

Keywords

  • P53
  • INHIBITORS
  • P53-MDM2
  • POTENT
  • DESIGN
  • ANTAGONISTS
  • BINDING
  • DOMAIN
  • MDMX
  • CHEMISTRY
  • CCDC 1847731: Experimental Crystal Structure Determination

    Neochoritis, D. (Contributor), Atmaj, J. (Contributor), Twarda-Clapa, A. (Contributor), Surmiak, E. (Contributor), Skalniak, L. (Contributor), Köhler, L. (Contributor), Muszak, D. (Contributor), Kurpiewska, K. (Contributor), Kalinowska-Tłuścik, J. (Contributor), Beck, B. (Contributor), Holak, T. A. (Contributor) & Dömling, A. (Contributor), University of Groningen, 6-Jun-2018

    Dataset

  • CCDC 1848075: Experimental Crystal Structure Determination

    Neochoritis, D. (Contributor), Atmaj, J. (Contributor), Twarda-Clapa, A. (Contributor), Surmiak, E. (Contributor), Skalniak, L. (Contributor), Köhler, L. (Contributor), Muszak, D. (Contributor), Kurpiewska, K. (Contributor), Kalinowska-Tłuścik, J. (Contributor), Beck, B. (Contributor), Holak, T. A. (Contributor) & Dömling, A. (Contributor), University of Groningen, 7-Jun-2018

    Dataset

  • CCDC 1848076: Experimental Crystal Structure Determination

    Neochoritis, D. (Contributor), Atmaj, J. (Contributor), Twarda-Clapa, A. (Contributor), Surmiak, E. (Contributor), Skalniak, L. (Contributor), Köhler, L. (Contributor), Muszak, D. (Contributor), Kurpiewska, K. (Contributor), Kalinowska-Tłuścik, J. (Contributor), Beck, B. (Contributor), Holak, T. A. (Contributor) & Dömling, A. (Contributor), University of Groningen, 7-Jun-2018

    Dataset

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