16 September 2015

Fragments vs ERK2

Extracellular-regulated kinase 2 (ERK2) is one of just two known substrates of the kinases MEK1 and MEK2, themselves the subjects of considerable clinical efforts to treat cancer. In a paper just published online in Bioorg. Med. Chem. Lett., Daniel Burdick and colleagues at Genentech describe how they have used FBLD to tackle ERK2.

A library of just 635 fragments was screened against the protein using STD NMR, yielding 54 hits, and SPR, yielding 78 hits. Thirteen of these came up in both assays, and compound 1 had the second-highest ligand efficiency. Not surprisingly, X-ray crystallography revealed that this purine binds to the hinge region of the kinase. The electron density also showed something else binding nearby, which the researchers interpreted as an imidazole molecule left over from the protein purification. Thus, they set out to grow their fragment in this direction.

The purine moiety of compound 1 was not well-suited for growing towards the imidazole, and purines have also been picked over extensively by numerous groups, so the researchers used scaffold-hopping to develop compound 3. This turned out to have acceptable affinity and dramatically improved ligand efficiency. Growing led to compound 14, and structural characterization of a related molecule confirmed that the added heterocycle bound in the same region as the originally observed imidazole.

Next, the researchers grew in a different direction, ultimately leading to compound 39, with low nanomolar potency. Although no cell activity or selectivity data are reported, the authors note that the series underwent further optimization that will be reported in future.

This is a nice, concise description of fragment-based lead discovery and optimization that incorporates multiple biophysical methods, structure-based drug design and modeling, and creative medicinal chemistry. It is not clear whether targeting ERK2 has advantages over MEK or RAF, but work like this is precisely what is needed to generate chemical probes to answer this question.

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