Last week the sixth FBLD meeting was held in Cambridge, MA. Like its predecessors in 2014, 2012, 2010, 2009, and 2008, this meeting was an enormous success, mixing more than 230 scientists with excellent (and liberal) food and drink. With 33 talks, more than 30 posters, and several vendor booths and workshops I won’t be able to do more than capture a few highlights.
The most striking feature for me was the number of success stories. This began with Steve Fesik’s keynote lecture, in which he discussed the MCL-1 inhibitors he and his team at Vanderbilt have discovered. When we highlighted his work last year he had reported low nanomolar inhibitors, but these did not have cell-based activity. His group has now optimized the molecules to low picomolar biochemical potency, low nanomolar cellular activity, and good activity in mouse xenograft models. This has not been easy: more than 2210 compounds were made, guided by 60 X-ray structures and dozens of pharmacokinetic experiments. It seems to be paying off though, and the researchers are developing biomarkers with the goal of advancing a compound into clinical testing.
Two other notable success stories about clinical candidates must be mentioned, though I’ll wait until publications come out before going into detail. Kathy Lee described how she and her colleagues at Pfizer chose a fragment that was less potent and ligand-efficient than other hits due to its interesting binding mode and were able to advance it to PF-06650833, an IRAK4 inhibitor with potential for inflammatory diseases. And Wolfgang Jahnke discussed how he and his colleagues at Novartis were able to discover and advance ABL001, an allosteric inhibitor of BCR-ABL, despite having the project halted twice – a reminder that persistence is essential.
Several other success stories have been covered at least in part on Practical Fragments, including inhibitors against PDE10A (presented by Izzat Raheem of Merck), Dengue RNA-dependent RNA polymerase (presented by Fumiaki Yokokawa of Novartis), lipoprotein-associated phospholipase A2 (presented by Phil Day of Astex), and BACE1 (presented by Doug Whittington of Amgen).
Crystallography was another theme, and several of the success stories relied on crystallographic fragment screening. Frank von Delft of the Structural Genomics Consortium described developments that allow screening 1000 crystals per week at Diamond’s Xchem facility in the UK, which include acoustic dispensing of compounds into crystallization drops – while carefully avoiding hitting the crystals head-on.
Several computational talks reported results that run contrary to conventional wisdom. Vickie Tsui of Genentech discussed their CBP bromodomain program (which we recently discussed here). Several water molecules form a highly ordered network in the protein, and a WaterMap analysis suggested that these were high-energy and that displacing them would lead to an enhancement in activity. Unfortunately this turned out not to be the case, though the researchers were able to get to low nanomolar inhibitors by growing towards a different region of the protein.
Li Xing mined the Pfizer database of 4000 kinase-ligand structures to extract 595 unique hinge binders. Not surprisingly, some of these – such as adenine and 7-azaindole – bound to multiple kinases, but 427 were complexed to just a single kinase. Hinge binders typically form 1 to 3 hydrogen bonds to the protein, and while there didn’t seem to be a correlation between the number of hydrogen bonds and potency, more hydrogen bonds did correlate – perhaps counterintuitively – with lower selectivity. To the extent that hydrogen bonds are thought of as enthalpic interactions, this further muddies the argument that enthalpy and entropy can be useful in drug design.
On a more positive note, Sandor Vajda (Boston University) suggested that, according to analyses done in FTMap, perhaps 60-70% of protein-protein interactions may be druggable – as long as we accept that this may require building larger molecules than commonly accepted. And Chris Radoux (Cambridge Crystallographic Data Centre) discussed the computational tool for characterizing hotspots that we previously covered here; a web server for easy search should be available soon.
Library design was also a key topic. Richard Taylor of UCB described his analysis of all FDA-approved drugs, which revealed >350 ring systems. Interestingly though, 72% of drugs discovered since 1983 rely exclusively on ring systems used prior to that date. Clearly there is plenty of untapped chemical real estate.
But getting there won’t necessarily be easy. David Rees stated that 33 fragments recently added to the Astex library required 13 different reaction types. Importantly, many of the fragment to lead successes at Astex have required growing the fragment from the carbon skeleton rather than from more synthetically tractable heteroatoms. Knowing in advance how to do this with every new member of a fragment library should make life much easier in the long run, though it is a serious challenge for chemists.