Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial ChemistryHartman, 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 journal › Article › Academic › peer-review
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.
|Number of pages||6|
|Journal||Bioorganic & Medicinal Chemistry Letters|
|Publication status||Published - 14-May-2020|
- Protein-protein interactions, DCC, hit-identification strategy, small-molecule stabilizers, INHIBITORS, IDENTIFICATION, BINDING, MODULATORS