CHI’s Drug
Discovery Chemistry (DDC) meeting took place last week in San Diego. I think
this was the largest yet, with >825 attendees, a third from outside the US,
and nearly 70% from industry. The initial DDC meeting in 2006 had just four
tracks, of which FBDD is the only one that remains. This one had nine tracks
and four one-day symposia, so it was obviously impossible to see everything. Like last year, I’ll just stick to broad themes.
Success Stories
As always, clinical compounds received deserved attention. Among two I’ve
covered recently, Paul Sprengeler described eFFECTOR’s MNK1/2 inhibitor eFT508,
while Wolfgang Jahnke discussed Novartis’s allosteric BCR-ABL1 inhibitor ABL001.
As previously mentioned, ABL001 is a case study in persistence: the project
started in stealth mode and was put on hold a couple times until seemingly
intractable problems could be overcome.
Another story
of persistence, albeit with a less happy outcome, was presented by Erik Hembre,
who discussed Lilly’s BACE1 program. Teddy wrote about their first
fragment-derived molecule to enter the clinic, LY2811376, back in 2011.
Unfortunately this molecule showed retinal toxicity in three-month animal
studies, so the researchers further optimized their molecule to LY2886721,
which made it to phase 2 studies before dropping out due to elevated liver
enzymes. Reasoning that a more potent molecule would require a lower dose and
thus lower the risk of toxicity, the researchers used structure-based drug
design to get to picomolar LY3202626, which also made it to phase 2 before being
scuttled due to the apparent invalidation of BACE1 as an Alzheimer’s disease
target.
Talks on BCL2
and MCL1 inhibitors from Vernalis, AstraZeneca, and Servier all involved fragments
in some capacity, but unfortunately they were in the protein-protein
interaction track which was held concurrently with the FBDD session I was
chairing. Suffice it to say you can expect to hear more about the phase 1
compounds AZD5991 and S654315.
A few earlier-stage success stories included Till Maurer’s discussion of the Genentech USP7 program
(see here), Santosh Neelamkavil on Merck’s Factor XIa inhibitors, and Rod
Hubbard on Vernalis DYRK1A, PAK1, and LRRK2 inhibitors. We have previously
written about how displacing “high-energy” water molecules can be useful, and this tactic was used by Sven Hoelder at the Institute of Cancer Research for their BCL6
inhibitors. Last week we highlighted halogen bonds, which proved important for
transforming molecules that simply bind to MEK1 to molecules that bind and inhibit the protein, as
described by AstraZeneca’s Paolo Di Fruscia.
Methods
The MEK1 story
Paolo told began with a very weak (0.45 mM) fragment that the team was able to
advance to 300 nM in the absence of structure, though they did eventually
obtain a crystal structure that supported further optimization. On the topic of
crystallography, Marc O’Reilly discussed the Astex MiniFrag approach, which we
recently wrote about here. Only a couple of these fragments contain a bromine
atom, but Marc did mention that, of the 10,051 X-ray complexes solved at
Astex, a number show halogen bonds, including some to the hinge region in
kinases.
At FBLD 2018 Astex’s
Chris Murray showed the first cryo-EM structure of a fragment bound to a
protein, and Marc confirmed that they have now obtained structures of fragments
bound to two targets, with fragments as small as 120 Da and resolution as good
as 2.3 Å. They are increasing automation, with turnaround times of less than 24
hours in some cases. Santosh also mentioned that Merck is applying cryo-EM to
fragments.
Frank McCormick
(UCSF) highlighted multiple fragment-finding methods used to discover
inhibitors against RAS family proteins, which are responsible for more than a
million cancer deaths each year. In addition to stalwarts such as
crystallography and NMR, these include less common methods such as Tethering and
the second harmonic generation (SHG) approach for detecting conformational
changes used by Biodesy. RAS was reported as a cancer driver almost forty years
ago, but only now are the first direct inhibitors entering the clinic – a testimony
to both the challenging nature of the target and how far we’ve come.
SHG and
Tethering were also highlighted elsewhere: Charles Wartchow described how SHG
identified 392 hits from a collection of 2563 fragments against an E3 ligase
bound to a target protein at Novartis, while Michelle Arkin described her use
of Tethering at UCSF to find molecules that could stabilize a complex of 14-3-3
bound to a specific client protein (see here).
An effective sponsored
talk was presented by Björn Walse of SARomics Biostructures and Red Glead
Discovery, who described weak affinity chromatography (WAC). Once they saw the
schedule for DDC, they looked for a target that would be presented shortly
before their presentation, and chose the protein USP7 as a test case. Beginning
in January, they screened a library of 1200 fragments to obtain 34 hits, of
which 7 confirmed in a thermal shift assay. This led to an SAR-by-catalog
experiment, and 11 of the 31 fragments tested showed activity, as did a Genentech positive control compound.
All
methods can generate false positives and false negatives (see for example here and here), some of which were described in an excellent talk by Engi Hassaan of Philipps University. Engi discussed how
improving the sensitivity of an STD assay by decreasing salt concentration identified more fragments that had previously been found by
crystallographic screening. She also presented a case study of how introducing
a tryptophan residue into a small protein to facilitate purification led to
problems down the road when the tryptophan side chain blocked a key pocket in the crystal lattice. Gregg Siegal (ZoBio) also highlighted a case
where a fragment bound to the dimer interface in a crystal structure, whereas
in solution the fragment bound to the active site, as observed by NMR.
Finally, among
computational methods, Pawel Sledz (University of Zurich) gave a nice overview
of the SEED and AutoCouple methods, while Paul Hawkins (OpenEye) described
rapid searching of more than 10 billion chemical structures using ROCS (rapid overlay of
chemical features). SkyFragNet is looking closer with each passing year.
There is much
more to say, so please feel free to comment. Several good events are
still coming up this year, and mark your calendar for 2020, when DDC returns to
San Diego April 13-17!
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