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000599428 1001_ $$0P:(DE-H253)PIP1084441$$aVisser, Emira J.$$b0
000599428 245__ $$aFrom Tethered to Freestanding Stabilizers of 14‐3‐3 Protein‐Protein Interactions through Fragment Linking
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000599428 520__ $$aSmall-molecule stabilization of protein-protein interactions (PPIs) is a promising strategy in chemical biology and drug discovery. However, the systematic discovery of PPI stabilizers remains a largely unmet challenge. Herein we report a fragment-linking approach targeting the interface of 14-3-3 and a peptide derived from the estrogen receptor alpha (ERα) protein. Two classes of fragments—a covalent and a noncovalent fragment—were co-crystallized and subsequently linked, resulting in a noncovalent hybrid molecule in which the original fragment interactions were largely conserved. Supported by 20 crystal structures, this initial hybrid molecule was further optimized, resulting in selective, 25-fold stabilization of the 14-3-3/ERα interaction. The high-resolution structures of both the single fragments, their co-crystal structures and those of the linked fragments document a feasible strategy to develop orthosteric PPI stabilizers by linking to an initial tethered fragment.
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000599428 7001_ $$aJaishankar, Priyadarshini$$b1
000599428 7001_ $$0P:(DE-H253)PIP1029396$$aSijbesma, Eline$$b2
000599428 7001_ $$aPennings, Marloes A. M.$$b3
000599428 7001_ $$aVandenboorn, Edmee M. F.$$b4
000599428 7001_ $$0P:(DE-H253)PIP1080460$$aGuillory, Xavier$$b5
000599428 7001_ $$aNeitz, R. Jeffrey$$b6
000599428 7001_ $$aMorrow, John$$b7
000599428 7001_ $$aDutta, Shubhankar$$b8
000599428 7001_ $$0P:(DE-HGF)0$$aRenslo, Adam R.$$b9$$eCorresponding author
000599428 7001_ $$0P:(DE-HGF)0$$aBrunsveld, Luc$$b10$$eCorresponding author
000599428 7001_ $$0P:(DE-HGF)0$$aArkin, Michelle R.$$b11$$eCorresponding author
000599428 7001_ $$0P:(DE-H253)PIP1024092$$aOttmann, Christian$$b12$$eCorresponding author
000599428 773__ $$0PERI:(DE-600)2011836-3$$a10.1002/anie.202308004$$gVol. 62, no. 37, p. e202308004$$n37$$pe202308004$$tAngewandte Chemie$$v62$$x1433-7851$$y2023
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