Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry

Alwin M Hartman; Walid A M Elgaher; Nathalie Hertrich; Sebastian A Andrei; Christian Ottmann; Anna K H Hirsch

doi:10.1021/acsmedchemlett.9b00541

Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry

ACS Med Chem Lett. 2020 Feb 28;11(5):1041-1046. doi: 10.1021/acsmedchemlett.9b00541. eCollection 2020 May 14.

Authors

Alwin M Hartman^{1

2

3}, Walid A M Elgaher², Nathalie Hertrich², Sebastian A Andrei⁴, Christian Ottmann^{4

5}, Anna K H Hirsch^{1

2

3}

Affiliations

¹ Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.
² Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, 66123 Saarbrücken, Germany.
³ Department of Pharmacy, Saarland University, Campus Building E8.1, 66123 Saarbrücken, Germany.
⁴ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.
⁵ Department of Chemistry, University of Duisburg-Essen, 47057 Essen, Germany.

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 (K _D 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.