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

Eline Sijbesma; Kenneth K Hallenbeck; Sebastian A Andrei; Reanne R Rust; Joris M C Adriaans; Luc Brunsveld; Michelle R Arkin; Christian Ottmann

doi:10.1021/acsmedchemlett.1c00088

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

ACS Med Chem Lett. 2021 May 10;12(6):976-982. doi: 10.1021/acsmedchemlett.1c00088. eCollection 2021 Jun 10.

Authors

Eline Sijbesma¹, Kenneth K Hallenbeck², Sebastian A Andrei¹, Reanne R Rust¹, Joris M C Adriaans¹, Luc Brunsveld¹, Michelle R Arkin², Christian Ottmann¹

Affiliations

¹ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.
² Department of Pharmaceutical Chemistry and Small Molecule Discovery Center (SMDC), University of California, San Francisco 94134, United States.

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.