FBLD 2014, the fifth in an illustrious series of conferences, took place in Basel, Switzerland last week. Organizers
Wolfgang Jahnke (Novartis), Michael Hennig (Roche), and Rod Hubbard (University
of York & Vernalis) put together a fantastic event. With 35 talks, 45
posters, and more than 200 delegates, I won’t attempt to give more than a few
impressions here. In addition to Teddy’s (and others’) Tweets, Derek
Lowe put up several posts (see here, here, and here); please share your
thoughts below.
Harren Jhoti delivered a lively and
wide-ranging opening keynote summarizing the past 15 years of FBLD as viewed
from Astex. Among many other innovations, researchers there are responsible for
the Rule of 3, which has been the subject of some debate. Harren
emphasized that the “Voldemort Rule” should not be a strait-jacket. Like the
Kobayashi Maru, rules are there to be broken, though you need to be something
of a James T. Kirk to do so effectively.
Astex has produced what is likely the
largest collection of protein-fragment crystal structures, and Harren noted
that many proteins appear to have fragment binding sites outside the active
site: across 25 different proteins, the average number of total sites is slightly
greater than 2. Astex is increasingly targeting these sites for allosteric lead discovery.
The theme of crystallography carried
through the conference. As Armin Ruf (Roche) exhorted, “more crystals, more
structures.” One challenge is that not all crystal forms are suitable for fragments,
and it is not always clear from the outset which forms will work. Armin
described their chymase project in which an initial crystal form gave 8 fragment
structures, but additional crystal forms allowed them to obtain 6 more. Without
the different crystal forms these later fragments would have been crystallographic false
negatives, yet the potential of different crystal forms to reveal more hits is
under-appreciated: Armin noted that the majority of recent fragment papers
reported using only a single crystal form.
The importance of crystallography was
emphasized again by Nick Skelton (Genentech), who discussed their NAMPT program
(which we covered here). In this project, which utilized dozens of crystal
structures, a single atom change to a fragment could completely and
unpredictably alter the binding mode.
Obtaining a good crystal is not necessarily
easy, though. Andreas Lingel (Novartis) described their efforts to produce a
form of B-RAF that would diffract to higher resolution and allow fragment soaks
(as opposed to co-crystallization). They tried reducing the “surface entropy”
by mutating glutamate and lysine residues to alanine, but only one of a dozen or so mutants expressed well and gave
superior crystals. Although this turned out to be useful, the team is still at
a loss to explain why the specific mutants are effective.
Continuing the theme of crystallography,
Matt Clifton (Beryllium) described what looks to be a significant advance for
the protein MCL-1. (This is a collaboration with the Broad Institute, and we
previously noted some of their progress here.) The researchers have developed a
maltose-binding protein (MBP) fusion of this oncology target that diffracts to
1.9 Å in the absence of any ligand. (MBP fusions are used to help crystallize challenging
proteins.) Since they developed this construct in May of this year, the researchers have
already solved more crystal structures than had been reported publicly to date,
and uncovered some interesting findings. For example, the initial fragment that
Steve Fesik’s group found binds in a similar manner to one of his more potent later
leads, as does one of the AbbVie fragments; however another AbbVie fragment
binds in a somewhat different fashion than the elaborated lead.
The subject of how to effectively sample
chemical space was another theme, and to this end Alison Woolford (Astex)
proposed the concept of a “minimal pharmacophore”: the minimal interactions necessary to drive fragment binding. Researchers at Astex have
systematically cataloged several dozen of these, which include such simple
entities as amines, acids, aromatic chlorides, and more abstract concepts such
as a 1-bond donor-acceptor (think pyrazole). Alison showed an interesting graph
with targets on the y-axis and minimal pharmacophores on the x-axis which
revealed some obvious patterns such as the preference of donor-acceptor minimal
pharmacophores by kinases, but there were unexpected features as well. In a
sense, this is an empirical realization of early docking studies, but it also
has interesting implications for library design. For example, Alison suggested
avoiding fragments with more than one minimal pharmacophore, as these will not
be able to effectively sample as many different sites on a protein: with two
pharmacophores, a fragment would be limited to binding sites having matching
recognition elements to both rather than just one. This idea ties in with the
concept of molecular complexity, but from a more chemocentric point of view.
On the subject of chemistry, Dalia Hammoudeh
(St Jude’s Hospital) gave a lovely talk on her experiences developing
allosteric inhibitors of DHPS, an antibiotic target. Among other fragment hits
from the Maybridge library, one was ostensibly 4-trifluoromethylbenzylamine,
but turned out to actually be the Schiff base of this with the corresponding
aldehyde. Yet another reminder to always carefully check what you think you
have.
Practical
Fragments has previously discussed the Genentech
MAP4K4 program (here and here), and Terry Crawford gave a nice summary. One of
the challenges they faced was that their initial leads had excellent brain
penetration, leading to animal toxicity. This forced them to increase size and
polar surface area. Although it was problematic in this case, this emphasizes
how small and drug-like fragment-derived leads can be. Indeed Vicki Nienaber,
who was a prime mover behind the original FBLD 2008 meeting, has devoted much
of her efforts at Zenobia to CNS targets.
Finally, Derek Lowe (Vertex) gave a
rollicking history of the drug industry, ending with his view of where
fragments fit in. He noted that chemists – Valinor not withstanding – play a
central role, and in that sense the field is a departure from the general trend
of the past decade or so. It still remains to be seen how many of the 30+molecules FBLD has delivered to the clinic will come out the other side, but at
least for now the field is thriving. As Chris Lipinski stated last year, “if I
had to single out one technology that really took me by surprise and has been
very successful, it has been fragment screening.”
4 comments:
I will be posting my more esoteric thoughts on Wednesday. And some pictures of the meeting/Basel.
The 'minimal pharmacaophore' concept has some similarity to the idea of defining molecular complexity in terms of extent of substitution (see http://fbdd-lit.blogspot.com/2009/01/molecular-complexity.html) and some of the thinking behind 'needle screening' (see http://dx.doi.org/10.1021/jm000017s) which actually predated the Hann molecular complexity model even though the authors of the article did not actually use the term 'molecular complexity'.
On an unrelated note, it would be good for the folk who weren't at the conference to be able to see the slide decks. Here's a good way to do this: http://lanyrd.com/
I agree with Pete on one point. If you present slides in public, they are public property and they should be made available. However, I don't know if I agree they should be made available to non-conference goers.
Strange rendering... Anyone else having the page render the bottom half of one or two words, with the impression there are several paragraphs? This is based on the spacing and font size.
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