Fragment-based Differential Targeting of PPI Stabilizer Interfaces

J Med Chem. 2020 Jul 9;63(13):6694-6707. doi: 10.1021/acs.jmedchem.9b01942. Epub 2020 Jun 23.


Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This X-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / chemistry
  • 14-3-3 Proteins / metabolism*
  • Drug Design
  • Models, Molecular
  • Protein Binding / drug effects
  • Protein Conformation
  • Small Molecule Libraries / pharmacology*


  • 14-3-3 Proteins
  • Small Molecule Libraries