CHI’s Drug Discovery Chemistry
(DDC) meeting was held last week in San Diego. The event continues to grow, and
this year hosted some 800 attendees, three quarters from the US and two thirds
from biotech or pharma. The first DDC meeting in 2006 had just four tracks, of
which FBDD is the only one that remains. The current event had nine tracks
and three one-day symposia. There was always something interesting happening,
and usually several – at one point three talks involving fragments were going
simultaneously. Like last year, I’ll just try to give a few impressions.
What struck me most was the
number of success stories, several involving clinical compounds. Last year we highlighted
Pfizer’s discovery of a chemical probe against ketohexokinase (KHK); Kim Huard
described how this was optimized to PF-06835919, the first and only KHK
inhibitor to enter the clinic, which is now in phase 2 trials for NAFLD.
Another phase 2 compound was
described by Paul Sprengeler (eFFECTOR Therapeutics). A handful of fragments designed
from published work were characterized crystallographically bound to the kinase
MNK1, and careful structure-based design resulted in eFT508, an MNK1/2
inhibitor which is being tested against various cancers.
A few years back we highlighted
Genentech’s work on the kinase ERK2. In a lovely example of fragment-assisted drug discovery, Huifen Chen told “the convoluted journey of an ERK2 fragment series
(with an HTS detour)”. SAR from the fragment series was used to inform the
optimization of an HTS series originating from partner Array BioPharma, and was
particularly useful for fixing some pharmacokinetic liabilities. Huifen emphasized
the importance of using information from multiple strategies, ultimately
leading to GDC-0994, which entered phase 1 trials for cancer.
Rounding up the list of clinical
compounds, I heard through the grapevine that AbbVie’s dasabuvir, approved for
hepatitis C, had fragments in its ancestry. I’d be interested to know more; though since success usually has many fathers, precise parentage can be tricky
to ascertain.
Earlier stage success stories
included the discovery of BI-9321, a highly selective inhibitor of NSD3-PWWP-1,
which binds to methylated lysine residues in proteins. Jark Böttcher described
how a collaboration between Boehringer Ingelheim and the Structural Genomics
Consortium started with NMR and DSF-based screens of 1899 fragments to identify
the cell-active chemical probe.
Jenny Viklund (Sprint Bioscience)
described the discovery of potent, selective inhibitors of MTH1, a potential
anti-cancer target. The project was successful, but unfortunately the molecules
did not have the desired effect in cancer cell lines; this and other evidence
helped to devalidate the target. Although undoubtedly disappointing, knowing
what not to pursue is still important, and who knows – perhaps the target will
turn out to be important in the future.
Finally, Steve Fesik (Vanderbilt)
described a number of success stories against the KRAS protein, one of the holy
grails of oncology. He also described how a fragment screen against a similarly
hot target, the transcription factor MYC, failed utterly – the numerous
compounds reported in the literature turned out to be artifacts or DNA
intercalators. However, colleague Bill Tansey found that MYC interacts with the
protein WDR5, and this protein-protein interaction turned out to be tractable,
ultimately yielding potent inhibitors. This is a useful reminder that even if
your target is not directly ligandable, biology is complicated enough that you
may be able to modulate it through one of its partners.
Success sometimes requires
breaking rules, as illustrated by the rule-of-5-defying drug venetoclax.
Indeed, as noted by AbbVie’s Phil Cox, 18 of the 76 oral drugs approved since
2014 are bRo5s (beyond rule of 5). But if you’re going to break rules you
should expect a harder path, and Phil described factors that correlate with
success. Pete Kenny will be delighted to know that this has resulted in a new
metric, AB-MPS, which is defined as the sum of the number of rotatable bonds,
aromatic rings, and the difference of the ClogD from 3; values less than 12 are
correlated with a higher probability of being orally bioavailable among AbbVie’s
bRo5s.
Former guest blogger Brian
Stockman described NMR-based functional screens he is doing with undergraduates
at Adelphi University. Library acquisition can be challenging for a small
organization, but happily Dean Brown at AstraZeneca has established an Open Innovation program for neglected diseases – if you’re interested and eligible
you can receive a high-quality 1963-fragment library plated and ready for
screening.
Of course there was plenty to
learn about fragment-finding methods too, both in talks and in a discussion
session led by Rod Hubbard (University of York and Vernalis). Microscale thermophoresis (MST) continues to
be controversial, with researchers from a couple companies commenting that it’s
fantastic the 20% of the time it works, while another company had success rates
of ~95%. Thermal shift assays were also contentious, though Fredrik Edfeldt’s
(AstraZeneca) method of adding urea or D2O (see here) to
improve the sensitivity created significant buzz.
Cryo-electron microscopy
continues to make rapid strides for structurally characterizing difficult
targets, such as membrane proteins. Christopher Arthur (Genentech) did not
downplay the many technical hurdles, particularly in sample preparation, but he
thought that 2 Å resolution structures would be routine within the next decade.
Although they have yet to analyze fragment binding, this is only a matter of
time.
Ben Cravatt (Scripps) discussed
ligand discovery on a proteome-wide scale using electrophilic fragments. His group has currently discovered more than 2000
ligandable cysteine residues in human cells – an exciting if daunting number of
potential new targets.
And in the category of now for
something completely different, Josh Wand (University of Pennsylvania)
described nanoscale encapsulation – in which individual proteins are confined
in reverse micelles suspended in liquid pentane; the low viscosity increases
tumbling time and thus resolution for NMR, while the miniscule volume increases
the concentration of protein and any accompanying fragments. This allows
detection of extraordinarily weak interactions (dissociation constants of
several hundred millimolar or worse). The technique is limited to very polar
fragments because less polar ones would diffuse into pentane, but it would be
interesting to see if a fluorocarbon replacement for the hydrocarbon allowed a wider range of fragments to be tested.
1 comment:
Thank you, Dan -- a great summary -- especially because I couldn't sit-in on the Fragment track myself. Thanks for a few ideas for 2019 as well. See you in Boston when you teach your FBDD course with Mary Harner from BMS again at our www.discoveryontarget.com event -Anjani (Lead Conference Director for www.drugdiscoverychemistry.com where the FBDD track took place).
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