%0 Journal Article
%A Visser, Emira J.
%A Jaishankar, Priyadarshini
%A Sijbesma, Eline
%A Pennings, Marloes A. M.
%A Vandenboorn, Edmee M. F.
%A Guillory, Xavier
%A Neitz, R. Jeffrey
%A Morrow, John
%A Dutta, Shubhankar
%A Renslo, Adam R.
%A Brunsveld, Luc
%A Arkin, Michelle R.
%A Ottmann, Christian
%T From Tethered to Freestanding Stabilizers of 14‐3‐3 Protein‐Protein Interactions through Fragment Linking
%J Angewandte Chemie
%V 62
%N 37
%@ 1433-7851
%C Weinheim
%I Wiley-VCH
%M PUBDB-2023-07400
%P e202308004
%D 2023
%X Small-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein. Two classes of fragments—a covalent and a noncovalent fragment—were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERα interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37455289
%U <Go to ISI:>//WOS:001040530100001
%R 10.1002/anie.202308004
%U https://bib-pubdb1.desy.de/record/599428