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. 2010 Nov 14;46(42):8020-2.
doi: 10.1039/c0cc02969f. Epub 2010 Sep 20.

Profiling Small Molecule Inhibitors Against Helix-Receptor Interactions: The Bcl-2 Family Inhibitor BH3I-1 Potently Inhibits p53/hDM2

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Free PMC article

Profiling Small Molecule Inhibitors Against Helix-Receptor Interactions: The Bcl-2 Family Inhibitor BH3I-1 Potently Inhibits p53/hDM2

Jason R Porter et al. Chem Commun (Camb). .
Free PMC article

Abstract

We validate a practical methodology for the rapid profiling of small molecule inhibitors of protein-protein interactions. We find that a well known BH3 family inhibitor can potently inhibit the p53/hDM2 interaction.

Figures

Fig. 1
Fig. 1
Specificity of helix–receptor interactions. (a) Schematic for the cell free interrogation of helix–receptor interactions resulting in interaction dependent luminescence. (b) (i) BIM (dark grey)/Bcl-xL (light grey) (ii) BIM (dark grey)/BFL (light grey), (iii) p53 (dark grey)/hDM2 (light grey), and (iv) Hif-1α (dark grey)/p300 (light grey). (c) Luminescence of co-translated helix–Nfluc and Cfluc–receptor interactions for all 18 pairs.
Fig. 2
Fig. 2
Interrogation of inhibitors of helix–receptor interactions. (a) Inhibition of the interaction of p53 with hDM2 and hDM4 by enantiomers of nutlin-3. (b) Inhibition of the interaction of Bcl-2 and Bcl-xL with the BIM BH3 domain upon addition of free BIM peptide.
Fig. 3
Fig. 3
Inhibition profile of (−) Nutlin, ABT-737, and ABT-263 against a panel of 6 helix/receptor interactions as well as the Fos/Jun leucine zipper and luciferase controls. All inhibition experiments were performed at 100 μM of the indicated compound.
Fig. 4
Fig. 4
(a) Inhibition profile of BH3I-1 (100 μM) against the PPI panel. (b) Fluorescence polarization experiment with fluorescein labeled p53-peptide and mDM2 with added BH3I-1 (400 μM to 391 nM) resulting in a Kd = 5.3 μM.

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