Fig. 2: SAR around analog 1 results in improved stabilizer 30.
From: Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity
a Crystal structure of compound 1 (blue sticks) in complex with 14-3-3σ (white surface) and ChREBPα (red sticks and surface). Final 2Fo-Fc electron density contoured at 1.0 σ. b Interactions of 1 (blue sticks) with 14-3-3σ (white) and ChREBPα (red) residues (relevant side chains are displayed in stick representation, polar contacts are shown as black dashed lines). c FA 2D protein titration of 14-3-3β in FITC-labeled ChREBPα peptide (10 nM) and varied but fixed concentrations of 1 (0–500 µM) (mean, n = 2), including the cooperativity factor (α) determined by fitting, using a thermodynamic equilibrium model27 and intrinsic affinity of 1 to 14-3-3 (KDII). Source data are provided as a Source Data file. d Structure and activity analogs of 1. The two best compounds are marked in cyan and yellow. EC50 in parenthesis with mean ± SD, n = 2 (IA = inactive). For FA titration graphs see Supplementary Figs. 4, 5. e, f Crystallographic overlay of 1 (blue sticks) with 30 (yellow sticks) in complex of 14-3-3σ (white cartoon) and ChREBPα (red cartoon). g Interactions of 30 (yellow) with 14-3-3 σ (white) and ChREBPα (red) (relevant side chains are displayed in stick representation, polar contacts are shown as black dashed lines).
