When you consider how vast the chemical space is and how restricted the topology and chemical environment of a specific pocket in a protein is, it’s quite surprising we can find molecules that the protein was not evolved to bind that can nonetheless bind and inhibit it potently. It is therefore even more surprising when a single molecule can potently hit two completely unrelated (by sequence, by structure and by function) proteins. Thus, when two independent groups publish such dual kinase/bromodomain inhibitors a week a part from each other, the mind reels.
Stability and structural recovery of the tetramerization domain of p53-R337H mutant induced by a designed templating ligand
S. Gordo et al. implement a new strategy for preventative anti-cancer therapeutics. R337H is the most frequent inherited mutation in p53, “The guardian of the genome”, and is associated with wide spectrum of cancer forms. The mutation is believed to destabilize the native tetramer form of p53. In this study the researchers designed a small molecule that reconstitutes tetramerization of such a mutant. By Nir London.