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Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry

Hartman, A. M., Elgaher, W. A. M., Hertrich, N., Andrei, S. A., Ottmann, C. & Hirsch, A. K. H., 14-May-2020, In : Bioorganic & Medicinal Chemistry Letters. 11, 5, p. 1041-1046 6 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Alwin M. Hartman
  • Walid A. M. Elgaher
  • Nathalie Hertrich
  • Sebastian A. Andrei
  • Christian Ottmann
  • Anna K. H. Hirsch

Protein-protein interactions (PPIs) play an important role in numerous biological processes such as cell-cycle regulation and multiple diseases. The family of 14-3-3 proteins is an attractive target as they serve as binding partner to various proteins and are therefore capable of regulating their biological activities. Discovering small-molecule modulators, in particular stabilizers, of such complexes via traditional screening approaches is a challenging task. Herein, we pioneered the first application of dynamic combinatorial chemistry (DCC) to a PPI target, to find modulators of 14-3-3 proteins. Evaluation of the amplified hits from the DCC experiments for their binding affinity via surface plasmon resonance (SPR), revealed that the low-micromolar (K-D 15-16 mu M) acylhydrazones are 14-3-3/synaptopodin PPI stabilizers. Thus, DCC appears to be ideally suited for the discovery of not only modulators but even the more elusive stabilizers of notoriously challenging PPIs.

Original languageEnglish
Pages (from-to)1041-1046
Number of pages6
JournalBioorganic & Medicinal Chemistry Letters
Volume11
Issue number5
Publication statusPublished - 14-May-2020

    Keywords

  • Protein-protein interactions, DCC, hit-identification strategy, small-molecule stabilizers, INHIBITORS, IDENTIFICATION, BINDING, MODULATORS

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