Inhibition of murine double minute 2 (MDM2)-p53 protein−protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.

An in depth meta analysis of 131 fragment-to-lead case-studies has shown the importance of synthetic methods that allow carbon-centred synthetic elaboration in the presence of polar pharmacophores.

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Protein–protein interactions are difficult therapeutic targets, and inhibiting pathologically relevant interactions without disrupting other essential ones presents an additional challenge. Herein we report how this might be achieved for the potential anticancer target, the TPX2–importin-α interaction. Importin-α is a nuclear transport protein that regulates the spindle assembly protein TPX2. It has two binding sites—major and minor—to which partners bind. Most nuclear transport cargoes use the major site, whereas TPX2 binds principally to the minor site. Fragment-based approaches were used to identify small molecules that bind importin-α, and crystallographic studies identified a lead series that was observed to bind specifically to the minor site, representing the first ligands specific for this site. Structure-guided synthesis informed the elaboration of these fragments to explore the source of ligand selectivity between the minor and major sites. These ligands are starting points for the development of inhibitors of this protein–protein interaction.

. -The copper-free iododeamination using the flow technique significantly improves the yield over the corresponding batch procedures. A wide range of substrates is subjected to these conditions affording the products (II) in moderate to good yields. The most common by-product is the diaryl-diazene. Substrates (I) possessing an electron-withdrawing group in para-, meta-, or ortho-positions, all provide reasonable yields, even in the case of the sterically hindered anilines, e.g. (