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Recycle, recycle, recycle!

Worldwide Cancer Research funded scientist Dr John Spencer has unearthed a new role for seemingly redundant chemicals made in his lab during his cancer research experiments.

Along with his collaborators, Dr Spencer, from the University of Sussex has found a new purpose for molecules that were originally made for his Worldwide Cancer Research project. A series of oxazole fragments (small drug-like molecules) did not work as well as hoped on the original protein they were meant to target (a faulty form of p53 called p53-Y220C) which we discussed in a previous blog post.

However, undeterred, the team are big believers in ‘recycling’ (inside and outside the lab) and giving molecules a new purpose.  When a hunch made them test the potential drugs on a new ‘bromodomain’ they were amazed at the results.

Dr Spencer explains “Bromodomains are a class of druggable proteins (meaning scientists can make drugs that act directly on these proteins to only kill certain types of cells, such a cancer cells).  They are big targets in cancer and inflammation, and play an important role in the regulation of gene expression (turning genes on and off).

The molecules we had made were able to block a protein called PHIP(2).  PHIP2 is a biomarker – that is something that indicates that cancer is present in the body- and a potential target to treat melanoma skin cancer that has spread.”

Although these results are exciting, Dr Spencer added “They are preliminary findings, and the biological activity of the molecules is still rather weak, so more work is needed.  It is great, however, to show that we can recycle molecules and put them to exciting and unexpected new uses.”

The work, led by the Structural Genomics Consortium and Diamond Light Source partners (Paul Brennan and Frank von Delft), was recently published in the flagship Royal Society of Chemistry journal Chemical Science.
1. Transient Protein States for the Design of Small-Molecule Stabilizers of Mutant p53. Joerger, A. C.*; Bauer, M. R.; Wilcken, R.; Baud, M. G.; Harbrecht, H.; Exner, T. E.; Boeckler, F. M.; Spencer, J.; Fersht, A. R. Structure, 2015, 23, 2246–2255.
2. A Poised Fragment Library Enables Rapid Synthetic Expansion Yielding the First Reported Inhibitors of PHIP(2), an Atypical Bromodomain. Cox, O. B., Krojer, T.; Collins, P.; Monteiro, O.; Talon, R.; Bradley, A.; Fedorov, O.; Amin, J.; Marsden, B. D.; Spencer, J.; Von Delft, F.*; Brennan, P. E.* Chem. Sci. 2016, 7, 2322-2330.

Image: Image shows an oxazole fragment sat inside in the PHIP(2) bromodomain as described above.