Abstract
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.
Original language | English |
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Pages (from-to) | 1041-1046 |
Number of pages | 6 |
Journal | Bioorganic & Medicinal Chemistry Letters |
Volume | 11 |
Issue number | 5 |
DOIs | |
Publication status | Published - 14-May-2020 |
Keywords
- Protein-protein interactions
- DCC
- hit-identification strategy
- small-molecule stabilizers
- INHIBITORS
- IDENTIFICATION
- BINDING
- MODULATORS