Fragments in the Caribbean

Last week saw the inaugural Zing FBDD conference in Punta Cana, Dominican Republic. Zing has been around only since 2007, and seems to focus on small conferences in exotic locales. The benefit is that they are able to attract high-profile speakers, as illustrated by the group photo below. However, in an era of shrinking travel budgets, getting approval to attend a conference at a resort is becoming a bit more challenging. That said, participants enjoyed nearly 30 presentations and great discussion – think of a Gordon Conference without the dorms, and breaks on the beach.

My favorite “equation” from the conference comes from Mike Serrano-Wu of the Broad Institute:

Undruggable = Undone

This was supported by some nice work on the anti-cancer target MCL-1, which makes a protein-protein interaction that was widely consider undruggable just a few years ago. An ¹⁹F NMR fragment screen gave a hit-rate of around 10%, leading eventually to low nanomolar leads. Fragment optimization was facilitated by a new crystal form of the protein that allowed the team to rapidly generate over a dozen protein-ligand co-crystal structures. Rumor has it that more details on this will be disclosed at FBLD 2014 in Basel in September (there are still a few openings available, but register soon.)

MCL-1 also figured heavily in talks by Andrew Petros (AbbVie, see also here) and Steve Fesik (Vanderbilt, see also here), who described cell-permeable molecules with high picomolar activity in biochemical assays. Steve also discussed programs against Ras and RPA, both also using SAR by NMR. As Mike Shapiro (Pfizer) pointed out in his opening presentation, one of the breakthrough ideas of SAR by NMR was to screen a library more than once per target, the second time in the presence of a first ligand to identify another. It is nice to see this strategy continuing to deliver against difficult targets, though preliminary results of our current poll (right hand side of page) indicate that linking is not necessarily easy.

One of the payoffs of doing fragment screens for many years on dozens of targets is a rich internal dataset. Chris Murray (Astex) mentioned that company researchers have solved close to 7000 protein crystal structures, more than a third of them with fragment ligands. A cross-target analysis found that hits tended to be more planar (ie, less “three-dimensional”, with apologies to Pete Kenny) than non-hits. This was particularly true for kinases; for six protein-protein interactions (PPIs) there was no correlation between shape and hit rate. Although defining complexity is difficult, Chris provided evidence that 3D fragments tend to be both larger and more complex.

Rod Hubbard (University of York and Vernalis) mentioned that Vernalis has determined more than 4000 protein crystal structures. Since 2002, 2050 fragments have been screened against more than 30 targets. Based on “sphericality” – the distance from the rod-sphere principle component axis – hits against kinases are marginally less spherical, while PPI hits reflect the shape of the overall library. So, despite the current push for more three-dimensional fragments, it remains to be seen whether this will be useful.

Jonathan Mason (Heptares) described how successful fragment approaches can be against membrane proteins such as GPCRs. Anyone who has worked on these targets will know that the SAR can be razor sharp, and their surfeit of structures is helping to explain this. For example, although many of the protein-ligand interactions appear merely hydrophobic, some displace high-energy water molecules, which can be revealed by crystal structures of both the free and bound forms of the protein. Displacement of high energy water molecules also helps to explain some “magic methyl” effects.

Fragment-finding methods were not neglected. Jonathan mentioned that, for the A2A receptor, SPR identified only orthosteric ligands, while TINS identified only allosteric ligands – the orthosteric ligands were actually too potent to be detected by this technique. John Quinn (Takeda, formerly SensiQ) and Aaron Martin (SensiQ) also discussed SPR, and in particular how variable temperature SPR analyses could be used to rank ligands based on their enthalpic binding, though as Chris Murray warned, this information can be difficult to use prospectively.

I also learned that a selective BCL-2 inhibitor from Vernalis and Servier has just entered into Phase 1 clinical trials. This has been the result of a long-running collaboration that has required creativity on the part of the scientists and patience on the part of management.

There is much more to tell – for example Teddy's extended metaphor of the Silk Road (this one, not this one!) – but in the interest of space I’ll stop here. Feel free to comment if you were there (or even if you weren’t!)