Identification of a new p53/MDM2 inhibitor motif inspired by studies of chlorofusin

Abstract

Previous studies on the natural product chlorofusin have shown that the full peptide and azaphilone structure are required for inhibition of the interaction between MDM2 and p53. In the current work, we utilized the cyclic peptide as a template and introduced an azidonorvaline amino acid in place of the ornithine/azaphilone of the natural product and carried out click chemistry with the resulting peptide. From this small library the first ever non-azaphilone containing chlorofusin analogue with MDM2/p53 activity was identified. Further studies then suggested that the simple structure of the Fmoc-norvaline amino acid that had undergone a click reaction was also able to inhibit MDM2/p53 interaction. This is an example where studies of a natural product have led to the serendipitous identification of a new small molecule inhibitor of a protein-protein interaction

Cytotoxicity of Pyrazine-Based Cyclometalated (C^Npz^C)Au(III) Carbene Complexes: Impact of the Nature of the Ancillary Ligand on the Biological Properties

“…Compounds 1 – 3 and 5 and the free ligand L were screened as potential inhibitors using a fluorescence polarization assay as previously described. 57 Human MDM2 protein (residues 17–125) was used in the polarization assay, and the wild-type p53 peptide (residues 15–27) was used as a positive control. Among the three gold-based complexes and the free ligand screened at a concentration of 100 μM, only compounds 1 and 2 appeared to disrupt the MDM2–p53 interaction, highlighting first the relevance of the gold cation and second the impact of the ancillary ligand.…”

“…A number of synthetic molecules have been shown to take advantage of this binding epitope to inhibit the interaction between MDM2 and p53. 57,62 …”

Unveiling the “Three‐Finger Pharmacophore” Required for p53–MDM2 Inhibition by Saturation‐Transfer Difference (STD) NMR Initial Growth‐Rates Approach

“…The compounds were screened by using a fluorescence polarisation (FP) assay described previously . Human MDM2 protein (17–125) was used in the polarisation assay and the wild‐type p53 peptide (residues 15–27) was used as a positive control and had an half maximal inhibitory concentration (IC 50 ) of 14.45 μ m and K i of 1.82 μ m .…”

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

“…With the current increase in availability of both gene sequences and the knowledge of their functions in life‐forms ranging from bacteria to humans, there is clearly an unmet need for new, sequence‐specific, small‐molecule DNA probes . Significant variations in the cell‐uptake potential of molecular structures and pharmacokinetic differences will also require discovery and development of a diversity of different molecular systems for DNA recognition that do not currently exist …”