7ba9 › Citations

Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers.

Figure 1
Figure 2
Figure 3
Sijbesma E, Hallenbeck KK, Andrei SA, Rust RR, Adriaans JMC, Brunsveld L, Arkin MR, Ottmann C
OpenAccess logo ACS Med Chem Lett 12 976-982 (2021)
Related entries: 7b9m, 7b9r, 7b9t, 7ba3, 7ba5, 7ba6, 7ba7, 7ba8, 7baa, 7bab

Cited: 7 times
EuropePMC logo PMID: 34136078

Abstract

The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue" mode of action.

Reviews citing this publication (3)

  1. Molecular Glue Discovery: Current and Future Approaches. Dewey JA, Delalande C, Azizi SA, Lu V, Antonopoulos D, Babnigg G. J Med Chem 66 9278-9296 (2023)
  2. Protein-protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies. Lucero B, Francisco KR, Liu LJ, Caffrey CR, Ballatore C. Trends Pharmacol Sci 44 474-488 (2023)
  3. Contemporary biophysical approaches for studying 14-3-3 protein-protein interactions. Thurairajah B, Hudson AJ, Doveston RG. Front Mol Biosci 9 1043673 (2022)

Articles citing this publication (4)



Quick links