Last week CHI held Discovery on Target – virtually of course. There were 20 tracks over three days and more than 650 attendees, down
from 1100+ last year. Because the event was more fragmented (pun intended)
than the recent DDC, which had at most four parallel tracks, the Q&As and
discussions seemed smaller, though that could have just been the ones I attended.
On the other hand, one of the huge advantages of the format is being able to watch
concurrently scheduled talks later. More thoughts on virtual conferences are
here, and if you have not already done so please take our poll on the right
side of the page.
This conference has always been
more biology-focused than DDC, with tracks on antibodies,
immunology, NASH, gene therapy, disease modeling, and fibrosis, among others. But
there were also plenty of talks on targets and methodology, which is where I’ll
focus most of this post. Please add your highlights and thoughts in the
comments.
Julien Orts (ETH Zurich) presented
an update on his NMR2 method, which uses information from intermolecular
NOEs to computationally determine protein-ligand structures without requiring full
NMR assignment of the protein. We wrote about this technique in 2017 and at the
time we questioned how applicable it would be to fragments due to low affinities,
multiple binding modes, and fewer contacts. As it turns out, very: Julien described successes with proteins including HDM2, DsbA, bromodomains, and Pin1.
Even with as few as 10-12 intermolecular NOEs he has been able to get good agreement
with crystal structures. Currently he is applying this approach to SARS-CoV-2 proteins
as part of the COVID-19-NMR project.
William Pomerantz (University of
Minnesota Twin Cities) also presented NMR techniques. He is particularly known
for his protein-observed 19F (PrOF) NMR screening, in which fluorinated
tyrosine and tryptophan residues are introduced into proteins. Ligand binding changes
the chemical shifts of the fluorine atoms, and by varying the concentration of
the fragment, accurate dissociation constants can be determined. In early work,
a screen of 930 fragments in pools of 5 against BRD4 took 11 hours (and another
11 hours for deconvolution) and provided multiple hits. We’ve covered some of
his more recent work using shapely fragments here, and in unpublished work he
has been screening the dual-domain construct of BRD4 and finding fragments that
are ten-fold selective for one over the other bromodomain. He is further
improving throughput by screening two proteins simultaneously.
Rounding out NMR, Andrew Petros
(AbbVie) presented a beautiful fragment-to-lead success story on TNFα, a
trimeric cytokine that has been the subject of numerous (often unsuccessful)
lead-discovery efforts. A 2-dimensional NMR screen of 18,000 fragments gave
just 11 hits. Crystallography of one showed two copies binding in close proximity,
and linking these ultimately led to a low nanomolar binder. The series showed
high clearance and no oral bioavailability, so they performed additional screens
to identify different fragments that were ultimately advanced to potent
compounds with animal efficacy. I look forward to reading the paper when it is
published.
Finding fragments is important,
but so is avoiding artifacts, the subject of a talk by Samantha Allen (Janssen).
Around 2% of screening compounds can form small molecule aggregates that can interfere
with assays, and if these aren’t weeded out they can quickly overwhelm an assay.
Samantha described the use of resonance waveguide grating (RWG) technology, as
used in the Corning Epic BT. This label-free technology is similar to SPR, but RWG
can be run in 384 or 1536 well plates. Samantha showed that RWG compares favorably
to dynamic light scattering for detecting aggregates. It is also 4-5 times faster
and less prone to false-positives.
Covalent fragments were a theme
of last month’s DDC, and they were prominent here as well. Four years ago we highlighted
work out of Ben Cravatt’s lab doing covalent fragment screening in cells, but
this was a rather time-consuming process. Steve Gygi (Harvard) has streamlined activity-based
protein profiling and was able to screen 288 fragments in just 7 days and identify
more than 1500 modified cysteine residues.
Dan Nomura (UC Berkeley)
continued the theme with a wide-ranging presentation using chemoproteomics to
discover covalent ligands for a variety of targets, including new E3 ligases, which can
be used for developing targeted protein degraders. (Shameless plug/disclosure:
Dan Nomura is a founder of my company, Frontier Medicines, and we are actively
hiring across multiple positions and levels.)
Targeted protein degraders such
as PROTACs were the subject of one track at last year’s DoT meeting, and this year
two sequential tracks were devoted to the topic. As I suggested in 2018, fragments could
be ideal starting points given that high affinity is not always necessary. This
year, Stewart Fisher confirmed that he and his colleagues at C4 Therapeutics
often “detune” chemical matter, lowering the binding affinity to get
efficient degraders. That doing so can improve physicochemical properties is a
nice bonus.
Finally, although not directly
fragment-related, William Kaelin (Dana Farber Cancer Institute) gave an
inspiring talk on the discovery and development of MK-6482, an allosteric HIF2α
inhibitor in late-stage clinical trials for cancer linked to Von Hippel-Lindau
disease; data released just last week shows durable responses in patients with
kidney cancer. The science itself was lovely, but he reminded us of the ultimate
stakes: “It’s not about what journal your paper is published in or whether you
can fool reviewer 3, it’s about whether you publish things that are true and
robust and can be built upon by others.”
Words to live by.
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