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.
5 comments:
Looking forward to see Vanderbild's MCL1 inhibitors published. Hell of a target.
Thank you for this post. I missed portion of meeting and this is very accurate.
Teddy, Dan,
any news about the 2015 3D fragments challenge (Damian Young, if i recall correctly)?
Heard good reports about successes disclosed this year with NP-like fragts.
For anyone who would like to use the Fragment Hotspot Map web tool, this page (http://www.ccdc.cam.ac.uk/solutions/csd-discovery/applications/fragment-hotspots/) will have the link to it once it is live.
If you want to be notified once the web tool is live, send an email to fragment-hotspot-support@ccdc.cam.ac.uk and we will let you know
Hi anonymous,
As touched on a few weeks ago, it doesn't look like the Safran Zunft Challenge has been quite met. That said, as neither Teddy nor Damian were at FBLD 2016, I suggested postponing the decision to FBLD 2018.
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