Fragments 2024
Last week saw the first of four
dedicated fragment meetings this year: Fragments 2024, the 9th RSC-BMCS
Fragment-based Drug Discovery Meeting, was held in historic Hinxton Hall,
Cambridge, UK. I won’t attempt to cover the 17 talks, 40+ posters, and 20
exhibitors in detail but just try to hit on some broad themes.
One highlight was a talk by Chris
Swain, whose Cambridge MedChem Consulting has come up several times at Practical
Fragments. Chris has been systematically cataloging fragment hits reported
in the literature, and his database now includes >2500 fragments from
>300 papers that hit 265 targets. This has not been easy: as we’ve noted in
our annual F2L reviews, papers don’t always mention fragments in the title or
abstract; sometimes you need to dig deep into the experimental methods to find
out the origin of the initial hits, and even then there are questions of interpretation.
Chris noted that the the drug aprepitat originated from a fragment-like
pharamacophore extracted from a more complex literature compound. That story was published in 1998,
predating the term “fragment-based drug discovery,” but perhaps it would be
considered FBDD today.
The fragments themselves are a
diverse bunch, with an average Tanimoto similarity of just 0.09, but there are
small clusters. Looking at them in
more detail, the ten most common scaffolds are aromatic (benzene, indole), which is a departure from approved drugs. There is also
a significant fraction of charged molecules, including 298 acids and 348 basic
groups. About 10% of the fragments hit more than one target, exactly what
you would expect from the theory of molecular complexity.
Chris’s talk was followed by a
wide-ranging panel discussion that expanded on some of these themes. Solubility
was recognized as important, though with different techniques being more persnickety:
Justin Dietrich (AbbVie) noted that pre-screening is critical for SPR, but for
protein-detected NMR the protein is present at high enough concentrations to
act as a “phase transfer reagent.”
The topic of thermodynamics also
came up, with Chris Murray noting that Astex collects lots of ITC data but uses
it for assessing free energy (ΔG) values rather than enthalpic energy (ΔH) values.
Helena Danielson (Uppsala University) noted that the early correlation between
compound quality and enthalpy found with HIV protease inhibitors did not seem to
apply to other targets despite significant investment in collecting data at
multiple companies, as also noted by Chris Smith (Mirati) and Mike Hann (GSK).
Rod Hubbard (Vernalis) puckishly suggested that the study of ΔH had produced “more
heat than light.”
The topic of MiniFrags also came
up during the panel discussion. Chris Murray noted that they had been tried on
quite a few targets but, as Rod Hubbard confirmed, were more helpful in
identifying binding sites than providing starting points. But Chris Smith pronounced
himself a “complete convert” after a MiniFrag identified an induced pocket on a
previously intractable target where fragments (and other techniques) had
failed.
Covalent fragments also made
several appearances, with Jonathan Pettinger describing a phenotypic screen at
GSK looking for compounds that block the pro-inflammatory M1 polarization of
macrophages. After screening some 2000 covalent fragments they used chemoproteomics
to determine that one of the best compounds acted by modifying cysteine 817 of
the kinase JAK1. Interestingly, this is the same cysteine identified independently
by researchers from Vividion, which could speak to the centrality of this
target, the reactivity of this particular cysteine, or both.
Pursuing residues other than
cysteine is seen as difficult, with Mike Hann noting in the panel discussion
that these may require more extensive non-covalent interactions and
Chris Murray noting that the warheads themselves were less attractive. But these
challenges have not dissuaded Peter Cossar (Eindoven University of Technology),
who has introduced cysteine-reactive disulfide and lysine-reactive aldehyde
moieties into the same fragment to crosslink a 14-3-3 protein to substrate
ERRγ.
Another theme was screening crude
reaction mixtures in a “direct to biology” approach. Vernalis was an early adopter
with their off-rate screening, and a talk by Lucie Guetzoyan confirmed
that they are continuing to invest here not just with SPR but also with
affinity-selection mass spectrometry and X-ray crystallography. Lucie also
described using flow chemistry to enable sensitive organometallic chemistries such
as Grignard and Negishi couplings. John Spencer (University of Sussex) is also
using crude reaction screening by crystallography and thought the approach can compress
ten years worth of work into a few months.
As with most conferences these days
there were plenty of success stories. Martina Schaefer (Nuvisan) described the discovery
of the Bayer SOS1 inhibitor BAY-293, which we wrote about here. Anna Vulpetti
(Novartis) described the discovery of IL-1β inhibitors, which we wrote about
here. Nicola Wilsher (Astex) described the discovery of potent SHP2 inhibitors;
I’ll write more about these later. And Matthew Calabrese described the
discovery of allosteric activators selective for the γ3 subunit of AMPK, which
could avoid the cardiotoxicity seen with less selective molecules. Three HTS
screens had failed but fragments ultimately led to a potent tool molecule.
Interestingly, some of the HTS compounds were later found to be hits but had
been overlooked because they were so weak that they did not rise above the
noise of the assay.
Finally, Justin Dietrich described
several success stories, including against TNFα (which we wrote about here) as
well as CD40 ligand. Justin noted that FBLD is used alongside HTS and DEL at
AbbVie, and that the techniques can be complementary – a theme noted by several
others.
Despite being so intimately integrated
with other discovery approaches, FBLD continues to innovate and evolve and remain
sufficiently quirky that stand-alone meetings are still valuable and rewarding.
I’m looking forward to seeing what the next several meetings reveal.