- An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB—Utilizing a Reversible Covalent Tethering Approach
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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.
- Wolter, Madita,Valenti, Dario,Cossar, Peter J.,Hristeva, Stanimira,Levy, Laura M.,Genski, Thorsten,Hoffmann, Torsten,Brunsveld, Luc,Tzalis, Dimitrios,Ottmann, Christian
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p. 8423 - 8436
(2021/06/28)
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- PROTEIN-PROTEIN INTERACTION STABILIZERS
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Provided herein, inter alia, are stabilizers of protein-protein interactions and methods of identifying and using the same.
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- CRTH2 MODULATORS
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Modulators of CRTH2, particularly antagonists of CRTH2, that are useful for treating various disorders, including asthma and respiratory disorders are disclosed. The compounds fall within a genus described by formula I
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Page/Page column 152
(2010/04/27)
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- INDOLIZINE ACETIC ACID DERIVATIVES AS CRTH2 ANTAGONISTS
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The specific compounds of this list : {7-cyano-2-methyl-1-[4-(morpholine-4-sutfonyl)benzyl]indolizin-3-yl}acetic acid, {1 -(3-chloro-4-ethanesulfonylbenzyl)-7-cyano-2-methylindolizin-3-yl}acetic acid, {1-[3-chloro4-(morpholine-4-sulfonyl)benzyl]-7-cyano-2
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