Artificial Macrocycles as Potent p53-MDM2 Inhibitors

Natalia Estrada-Ortiz, Constantinos G. Neochoritis, Aleksandra Twarda-Clapa, Bogdan Musielak, Tad A. Holak, Alexander Dömling

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15 Citations (Scopus)
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Abstract

Based on a combination of an Ugi four component reaction and a ring closing metathesis, a library of novel artificial macrocyclic inhibitors of the p53-MDM2 interaction was designed and synthesized. These macrocycles, alternatively to stapled peptides, target for the first time the large hydrophobic surface area formed by Tyr67, Gln72, His73, Val93, and Lys94 yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using fluorescence polarization (FP) assay and 1H-15N two-dimensional HSQC nuclear magnetic resonance experiments.
Original languageEnglish
Pages (from-to)1025-1030
Number of pages6
JournalBioorganic & Medicinal Chemistry Letters
Volume8
Issue number10
DOIs
Publication statusPublished - 12-Oct-2017

Keywords

  • cancer
  • Macrocycles
  • MDM2
  • p53
  • protein-protein interaction
  • Ugi reaction
  • glycine
  • histidine
  • lysine
  • macrocyclic compound
  • protein inhibitor
  • protein MDM2
  • protein p53
  • protein p53 MDM2 interaction inhibitor
  • tyrosine
  • unclassified drug
  • valine
  • article
  • cyclization
  • drug potency
  • drug protein binding
  • drug structure
  • drug synthesis
  • fluorescence polarization
  • nitrogen nuclear magnetic resonance
  • physical chemistry
  • priority journal
  • protein protein interaction
  • proton nuclear magnetic resonance
  • ring closing metathesis
  • surface area
  • TRANSIENT PROTEIN STATES
  • MDM2-P53 INTERACTION
  • P53
  • ANTAGONISTS
  • DESIGN
  • CANCER
  • MDMX
  • CHEMISTRY
  • PEPTIDES
  • ROUTE

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