Fig. 1: Overview of the scaffold hopping approach. SAR and crystal structures of selected benzyl and aniline analogs.

a Crystal structure of compound 127 (yellow sticks) with 14-3-3σ (grey surface) and phospho-ERα peptide (orange sticks). Interacting aminoacids are shown as sticks and water molecules as red spheres (PDB 8ALW). b Chemical structure of compound 127 and ligand overlay of compound 127 and docking pose of the new MCR scaffold. c General multi-component reaction scaffold (MCR) based on the Groebke-Blackburn-Bienaymé (GBB) reaction and main points of variation. d Overview of general synthetic routes. Detailed experimental conditions are described in the SI. e Mass Spectrometry (MS) bar graphs at 1 μΜ. For each compound, time course experiments were performed with measurements at 1 h, 8 h, 16 h and 24 h. ERα data are shown with different colors for each compound, and apo data in grey. f Crystal structure overlay for compounds 1 (cyan sticks) (PDB 9I6Y) and 127 (yellow sticks) (PDB 8ALW) bound to 14-3-3σ (grey surface) /ERα (orange sticks). g Crystal structure of compound 1 (cyan sticks) (PDB 9I6Y) with 14-3-3σ/ERα. Interacting aminoacid residues are shown as sticks and interacting water molecules as red spheres. h, i Structural overlays of compounds 2 (brown sticks) (PDB 9I6Z), and 10 (dark red sticks) (PDB 9I72) with compound 1 (cyan sticks) (PDB 9I6Y).