8ARQ

Small molecular stabilizer for ERalpha and 14-3-3 (1080266)

Summary for 8ARQ

• Entry DOI: 10.2210/pdb8arq/pdb
• Descriptor: 14-3-3 protein sigma, Estrogen receptor, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: 14-3-3, eralpha, stabilization, covalent, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 27669.79

Authors

Visser, E.J.,Vandenboorn, E.M.F.,Ottmann, C. (deposition date: 2022-08-17, release date: 2023-09-20, Last modification date: 2024-10-09)

Primary citation

Konstantinidou, M.,Visser, E.J.,Vandenboorn, E.,Chen, S.,Jaishankar, P.,Overmans, M.,Dutta, S.,Neitz, R.J.,Renslo, A.R.,Ottmann, C.,Brunsveld, L.,Arkin, M.R.
Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3 sigma /ER alpha Protein-Protein Interaction from Nonselective Fragments.
J.Am.Chem.Soc., 145:20328-20343, 2023

PubMed Abstract: The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. The identification of suitable starting points for stabilizing native PPIs and their subsequent elaboration into selective and potent molecular glues lacks structure-guided optimization strategies. We have previously identified a disulfide fragment that stabilized the hub protein 14-3-3σ bound to several of its clients, including ERα and C-RAF. Here, we show the structure-based optimization of the nonselective fragment toward selective and highly potent small-molecule stabilizers of the 14-3-3σ/ERα complex. The more elaborated molecular glues, for example, show no stabilization of 14-3-3σ/C-RAF up to 150 μM compound. Orthogonal biophysical assays, including mass spectrometry and fluorescence anisotropy, were used to establish structure-activity relationships. The binding modes of 37 compounds were elucidated with X-ray crystallography, which further assisted the concomitant structure-guided optimization. By targeting specific amino acids in the 14-3-3σ/ERα interface and locking the conformation with a spirocycle, the optimized covalent stabilizer achieved potency, cooperativity, and selectivity similar to the natural product Fusicoccin-A. This case study showcases the value of addressing the structure, kinetics, and cooperativity for molecular glue development.

PubMed: 37676236
DOI: 10.1021/jacs.3c05161

Experimental method

X-RAY DIFFRACTION (1.4 Å)