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Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry.
Hartman, Alwin M Elgaher, Walid A M Hertrich, Nathalie Andrei, Sebastian A Ottmann, Christian Hirsch, Anna K H
Hartman, Alwin M
Elgaher, Walid A M
Hertrich, Nathalie
Andrei, Sebastian A
Ottmann, Christian
Hirsch, Anna K H
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2020-02-28
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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.
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ACS Med Chem Lett. 2020;11(5):1041-1046. Published 2020 Feb 28. doi:10.1021/acsmedchemlett.9b00541.
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en
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1948-5875