ml9b00541_si_001.pdf (2.7 MB)
Discovery of Small-Molecule Stabilizers of 14-3-3 Protein–Protein Interactions via Dynamic Combinatorial Chemistry
journal contribution
posted on 2020-03-09, 14:37 authored by Alwin
M. Hartman, Walid A. M. Elgaher, Nathalie Hertrich, Sebastian A. Andrei, Christian Ottmann, Anna K. H. HirschProtein–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.