Of the fragment-derived drugs that have entered the clinic, roughly half target protein kinases. Phil Hajduk (of SAR-by-NMR fame) and Irini Akritopoulou-Zanze provide a nice overview in a recent paper of how Abbott applies fragment-based approaches to this target class.
As anyone who works in the field of kinases can attest, there’s a lot of competition: the authors state that, since 2001, more than 10,000 patents or patent applications describing protein kinase inhibitors have been published. With so many inhibitors already identified, developing novel molecules is a particular challenge. This is somewhat due to the fact that most kinase inhibitors bind at least in part to the conserved purine binding site, or hinge-region. This is a thermodynamic hot-spot, usually accounting for 40-60% of the total binding energy for fully elaborated molecules. It is straightforward to carve out fragments that bind in this site from existing molecules, as shown in the figure.
But as also shown in the figure, this approach can create complicated IP, with dozens or even hundreds of overlapping patents covering the fragments. Of course, this doesn’t mean that clever medicinal chemistry can’t navigate the IP minefield, as examples described on this site from SGX and Astex have shown.
Nonetheless, the Abbott researchers decided to steer away from this hazard. They have designed and synthesized about 50 novel hinge-binders and over 5000 more elaborated molecules, and used these in their screens against kinases as well as other targets. The results are quite interesting.
First, many of the fragments show quite a bit of selectivity, hitting only one or two kinases out of a panel of 11 different kinases. In other cases, selectivity could be achieved through subsequent optimization, though in these cases the process was more often driven empirically than by structure-based design.
Another interesting observation is that the same fragment sometimes bound to different kinases in different fashions, or changed its binding mode during elaboration. This phenomenon has been previously reported by researchers at Vernalis.
The third observation is that, while these molecules exhibited a 10-fold enrichment against 13 different kinase targets compared to the generic Abbott screening collection, they also exhibited a 3-fold enrichment for 20 non-kinase targets. The authors suggest this is due to the fact that they may be acting as adenine mimetics, but it is also consistent with the Hann model of less complex fragments being able to bind to more targets (as discussed here and here).
Of course, fragment-based methods are not the only way to identify kinase inhibitors. As the authors note, “there has been almost universal success in the design and identification of potent kinase inhibitors.” Still, this brief review provides some practical advice on how fragment-based philosophies can complement more traditional lead discovery approaches.