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Fragment based protein‐protein interaction stabilizers via imine‐based tethering

DOI: 10.1002/anie.202008585 DOI Help

Authors: Christian Ottmann (Technische Universiteit Eindhoven) , Madita Wolter (Technische Universiteit Eindhoven) , Dario Valenti (Taros Chemicals GmBh) , Peter J. Cossar (Technische Universiteit Eindhoven) , Laura M. Levy (Taros Chemicals GmbH) , Stanimira Hristeva (Taros Chemicals GmbH) , Thorsten Genski (Taros Chemicals GmbH) , Torsten Hoffmann (Taros Chemicals GmbH) , Luc Brunsveld (Technische Universiteit Eindhoven) , Dimitrios Tzalis (Taros Chemicals GmbH)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Angewandte Chemie International Edition

State: Published (Approved)
Published: August 2020

Open Access Open Access

Abstract: Small‐molecule stabilization of protein‐protein interactions (PPI) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a ‘bottom‐up’ approach is largely unanswered. Here we report a novel concept for identifying initial chemical matter for PPI stabilization based on covalent imine forming fragments. The imine bond offers a covalent anchor for site‐directed fragment targeting, whereas its transient nature allows an efficient structure activity relationship analysis. This bond enables fragment identification and optimisation using protein crystallography. We report novel fragments which bind specifically to a lysine at the PPI interface of the p65 subunit‐derived peptide of NF‐κB with the adapter protein 14‐3‐3. Those fragments that subsequently establish contacts with the p65‐derived peptide, rather than with 14‐3‐3, efficiently stabilize the 14‐3‐3/p65 complex and offer novel starting points for molecular glues.

Journal Keywords: Imine Chemistry; Cooperative Effects; Fragment-based drug discovery; ligand design; 14-3-3

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: P11 at Petra III


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