Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface

Small‐molecule modulation of protein–protein interactions (PPIs) is one of the most promising new areas in drug discovery. In the vast majority of cases only inhibition or disruption of PPIs is realized, whereas the complementary strategy of targeted stabilization of PPIs is clearly under‐represente...

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Bibliographic Details
Published in:ChemMedChem Vol. 11; no. 8; pp. 911 - 918
Main Authors: Bier, David, Bartel, Maria, Sies, Katharina, Halbach, Sebastian, Higuchi, Yusuke, Haranosono, Yu, Brummer, Tilman, Kato, Nobuo, Ottmann, Christian
Format: Journal Article
Language:English
Published: Germany Blackwell Publishing Ltd 19.04.2016
Wiley Subscription Services, Inc
Subjects:
14-3-3 Proteins - chemistry
14-3-3 Proteins - metabolism
Adaptor Proteins, Signal Transducing - chemistry
Adaptor Proteins, Signal Transducing - metabolism
Biological Products - chemical synthesis
Biological Products - chemistry
Biological Products - pharmacology
Crystal structure
Crystallography, X-Ray
Diterpenes - chemical synthesis
Diterpenes - chemistry
Diterpenes - pharmacology
Dose-Response Relationship, Drug
Drug Stability
Glycosides - chemical synthesis
Glycosides - chemistry
Glycosides - pharmacology
Humans
Models, Molecular
Molecular Conformation
natural products
Protein Binding - drug effects
protein-protein interactions
Proteins
semi-synthesis
Small Molecule Libraries - chemical synthesis
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
small molecules
Structure-Activity Relationship
Tumor Cells, Cultured
X-ray protein crystallography
natural products
semi-synthesis
small molecules
X-ray protein crystallography
protein-protein interactions
ISSN:1860-7179, 1860-7187, 1860-7187
Online Access:Get full text
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Summary:Small‐molecule modulation of protein–protein interactions (PPIs) is one of the most promising new areas in drug discovery. In the vast majority of cases only inhibition or disruption of PPIs is realized, whereas the complementary strategy of targeted stabilization of PPIs is clearly under‐represented. Here, we report the example of a semi‐synthetic natural product derivative—ISIR‐005—that stabilizes the cancer‐relevant interaction of the adaptor protein 14‐3‐3 and Gab2. The crystal structure of ISIR‐005 in complex with 14‐3‐3 and the binding motif of Gab2 comprising two phosphorylation sites (Gab2pS210pT391) showed how the stabilizing molecule binds to the rim‐of‐the‐interface of the protein complex. Only in the direct vicinity of 14‐3‐3/Gab2pT391 site is a pre‐formed pocket occupied by ISIR‐005; binding of the Gab2pS210 motif to 14‐3‐3 does not create an interface pocket suitable for the molecule. Accordingly, ISIR‐005 only stabilizes the binding of the Gab2pT391 but not the Gab2pS210 site. This study represents structural and biochemical proof of the druggability of the 14‐3‐3/Gab2 PPI interface with important implications for the development of PPI stabilizers. A stabilizing influence: We have identified a semi‐synthetic, natural product protein–protein interaction (PPI) stabilizer that enhances the binding of the adapter protein 14‐3‐3 to oncogenic Gab2. Stabilization of this PPI is expected to attenuate the pro‐oncogenic activity of Gab2. Our molecule, ISIR‐005, represents chemical proof‐of‐principle for the druggability of the 14‐3‐3/Gab2 interface.
Bibliography:Deutsche Forschungsgemeinschaft (DFG)
ArticleID:CMDC201500484
istex:C3FF728521CC527547B9966196FFF1BBCB834A67
ark:/67375/WNG-9M83ZFT3-F
DFG Heisenberg program
DFG Excellence Initiative - No. GSC-4 SGBM; No. EXC 294 BIOSS
European Commission′s Horizon 2020 Marie Skłodowska-Curie action (MSCA) - No. PIAPP-GA-2011-286418 14-3-3Stabs
Deutsche Krebshilfe
Mildred-Scheel Program - No. 111815
Collaborative Research Center SFB1093
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SourceType-Scholarly Journals-1
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ISSN:1860-7179
1860-7187
1860-7187
DOI:10.1002/cmdc.201500484