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|Title:||Discovery of Small-Molecule Stabilizers of 14-3-3 Protein–Protein Interactions via Dynamic Combinatorial Chemistry|
|Author(s):||Hartman, Alwin M.|
Elgaher, Walid A. M.
Andrei, Sebastian A.
|Title:||ACS medicinal chemistry letters|
|Year of Publication:||2020|
|Publikation type:||Journal Article|
|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.|
|DOI of the first publication:||10.1021/acsmedchemlett.9b00541|
|URL of the first publication:||https://pubs.acs.org/doi/10.1021/acsmedchemlett.9b00541|
|Link to this record:||hdl:20.500.11880/29139|
|Date of registration:||14-May-2020|
|Faculty:||NT - Naturwissenschaftlich- Technische Fakultät|
|Department:||NT - Pharmazie|
|Professorship:||NT - Prof. Dr. Anna Hirsch|
|Collections:||UniBib – Die Universitätsbibliographie|
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