An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB-Utilizing a Reversible Covalent Tethering Approach

Madita Wolter, Dario Valenti, Peter J Cossar, Stanimira Hristeva, Laura M Levy, Thorsten Genski, Torsten Hoffmann, Luc Brunsveld, Dimitrios Tzalis, Christian Ottmann

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Protein-protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein-protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex.

Original languageEnglish
JournalJournal of Medicinal Chemistry
DOIs
Publication statusE-pub ahead of print - 2 Jun 2021

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