Ten years ago,
Vicki Nienaber (Zenobia) enlisted a small group of fellow enthusiasts to help her
organize an independent fragment-based lead discovery conference in San Diego.
That event was so successful that it was repeated in York in 2009, Philadelphia
in 2010, San Francisco in 2012, Basel in 2014, and Cambridge (USA) in 2016.
Last week, to celebrate its first decade, Derek Cole (Takeda), Rod Hubbard (University of York) and Chris Smith (COI) brought FBLD 2018 back to San Diego, along with some 200 fragment fans. With around 30 talks,
more than 40 posters, and nearly 20 exhibitors, I won’t attempt to present a
comprehensive overview, but just focus on broad themes.
Success Stories
I
estimate that, in 2008, 14 fragment-based programs had entered the clinic, none of which
had advanced beyond phase 2. That list has now grown to more than 40, so
naturally success stories were a focus.
Andy Bell
(Exscientia) discussed NMT inhibitors for malaria and the common cold (see
here); the AI-driven approach took < 500 molecules to get to molecules with
animal efficacy. Steve Woodhead (Takeda) revealed potent inhibitors of TBK1, a
kinase involved in the innate immune response. It took just three months to go from a
fragment hit to an animal-active lead, though unfortunately that molecule also
showed apparent on-target toxicity. And Rosa María Rodríguez Sarmiento (Roche)
described the discovery of COMT inhibitors (see here).
Mary Harner
(BMS) described the discovery of sub-micromolar KAT II inhibitors in just a few
months, enabled by parallel chemistry and the synthesis of 833 compounds.
Several series turned out to be aggregators, and BMS has instituted a routine
β-lactamase screen (an enzyme particularly sensitive to aggregators) to catch
these early.
Keith McDaniel
(AbbVie) described the discovery of the BET-family bromodomain inhibitor
ABBV-075. This program also made rapid progress: just
six months from the initial fragment hit, although the team did spend another
year trying to find better molecules. This effort eventually paid off, as the
same fragment has now led to a BD2-selective molecule, ABBV-744, that has
recently entered the clinic.
And Paul
Sprengeler (eFFECTOR) described the discovery of eFT508. This too was a rapid success: just 1 year and 170 compounds,
enabled by 30 co-crystal structures, and in the end a dozen molecules competing
for candidacy.
Notice that
many of these projects moved quickly. Feel free to send this summary to anyone
who worries that fragment programs move too slowly to be practical.
Technologies
Technologies
have always had a starring role in FBLD conferences, and this one was no
exception. Ben Cravatt (Scripps) discussed his fragment-based target discovery methods (see here and
here). As I speculated recently, he is now using these approaches to discover
new protein degraders. And his "fully functionalized fragments" are being adopted by others, as
described in a poster by Emma Grant and collaborators at GlaxoSmithKline and
University of Strathclyde.
Surface
plasmon resonance (SPR) was used routinely by many of the speakers, but there
is plenty of room for innovation. John Quinn (Genentech) described how to
extend kinetic measurements to the very fast and the very slow. John also noted
that gathering kinetic data earlier to deprioritize series with slow on-rates
may be wise. And for those who wonder about the limits of detection for SPR,
John measured the affinity of imidazole for NTA: just 13.6 mM!
Miles Congreve
(Sosei Heptares) described multiple methods applied to GPCR targets along with
a number of success stories. He also noted that, in the PAR2 program we
mentioned recently, fragments were able to identify a buried pocket that
could not be found using DNA-encoded libraries of several billion members,
presumably because the pocket would not be accessible to a DNA-bound ligand. Interestingly, this pocket could be detected computationally using FTMap, as shown in a poster presented by Amanda Wakefield (Boston University).
Pedro Serrano
(Takeda) described a variety of biophysical methods applied to GPCRs, the most
stunning of which is an SPR microscope capable of performing kinetic binding
assays on whole cells. He has tested this Biosensing Instrument on four
different GPCRs, and although there are technical challenges, the data seem usable.
But the light
shone most brightly on crystallography, illuminated by Stephen Burley (Protein
Data Bank) among others. In order to justify continued public funding and free
access (yes, there were suggestions to put the PDB behind a paywall), the PDB
was asked to demonstrate its usefulness to society. Their analysis found that
of the 210 new molecular entities (NMEs) approved by the FDA from 2010 through
2016, 184 had PDB entries for the target and/or the NME – for a total of 5914
structures, 95% of which were crystallographic. Most of these structures had
been deposited at least 10 years before the drug was approved, so in many cases
they probably played an important role.
John Barker
described how Evotec has jumped into high-throughput screening by
crystallography in a collaboration with the Diamond Light Source, which is now
capable of doing 700 soaks per day. They have run 10 screens over the past 18
months with a small library of 320 fragments, with hit rates typically around
8%.
We have
written about how high concentrations can improve success in crystal soaking
experiments, and both Chris Murray and Dominic Tisi of Astex described how
they’ve taken this to an extreme: 1 M soaks, with the fragment dissolved
directly in the soaking solutions. Obviously this requires highly soluble
fragments, so they’ve built a library of 81 “MiniFrags” having on average just
6.4 non-hydrogen atoms. They have tested these against five targets that
diffract to high resolution and have found impressively high hit rates of
20-60%, compared to the 2-20% in the original 100 mM soaks for the same
targets. Some of the sites are exploited by previously reported inhibitors or
substrates, while others are new. And while the “universal fragment”
4-bromopyrazole did well, 1,2,3-triazole did even better – binding to all five
targets in a total of 22 sites.
Crystallographers
should not become complacent. Gabe Lander (Scripps) gave an update on cryo-EM,
which we’ve written about here. The number of cryo-EM structures deposited in the PDB
eclipsed those from NMR in 2016, and resolution continues to improve, with the
current (as of late September) record at 1.56 Å. Still, the technique is not
nearly as fast as crystallography: best case is 8 hours from data collection to
refinement, although Gabe did think that 10 structures per day would be
possible within the next few years. And Chris Murray noted that, if present
trends continue, “we’ll all be doing cryo-EM in five years’ time.” Backing this
up, he showed what I suspect may be the first clear density map of a fragment
bound to a test protein.
This was the
last major fragment event of the year, but next year’s calendar is already
shaping up nicely. And mark your calendar for September 2020, when FBLD 2020
will move to the original Cambridge (UK).
1 comment:
Thanks Dan for the informative overview and your support for the conference. Derek, Rod and I viewed this opportunity to put something back into to the fragment community as an honor and a privilege. The FBLD conference is a highlight in the calendar and a key element in the scientific discussion around fragments. We would like to thank all the speakers, poster presenters, exhibitors and the delegates for making the conference a special occasion. As Derek and I pass the baton onto the Cambridge UK based organizing team for 2020 we look forward to FBLD2020!
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