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doi:10.22028/D291-30923
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. Hertrich, Nathalie Andrei, Sebastian A. Ottmann, Christian Hirsch, Anna K. H. |
Language: | English |
Title: | ACS medicinal chemistry letters |
Volume: | 11 |
Issue: | 5 |
Startpage: | 1041 |
Endpage: | 1046 |
Publisher/Platform: | ACS |
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 http://dx.doi.org/10.22028/D291-30923 |
ISSN: | 1948-5875 |
Date of registration: | 14-May-2020 |
Faculty: | NT - Naturwissenschaftlich- Technische Fakultät |
Department: | NT - Pharmazie |
Professorship: | NT - Prof. Dr. Anna Hirsch |
Collections: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
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