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

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

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

6 Citaten (Scopus)
163 Downloads (Pure)

Samenvatting

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 (KD 15-16 μM) 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.

Originele taal-2English
Pagina's (van-tot)1041-1046
Aantal pagina's6
TijdschriftBioorganic & Medicinal Chemistry Letters
Volume11
Nummer van het tijdschrift5
DOI's
StatusPublished - 14-mei-2020

Citeer dit