Last week the CHI Drug Discovery
Chemistry (DDC) meeting was held in San Diego, and it was the largest ever,
with more than 850 participants, 87% of whom attended in person, up from 70%
last year. I won’t attempt to cover all twelve tracks, but will just touch on some
of the main themes.
Covalent fragments
Brent Martin kicked off a session
devoted to covalent modifiers by describing the in-cell proteome-wide covalent
ligand discovery done at Scorpion Therapeutics. Brent emphasized the importance
of measuring kinact/Ki to characterize compounds, and he went
so far as to say he would recommend rejecting papers that report only IC50
values. He emphasized some of the challenges finding low-affinity fragments
(with high Ki values) that are not overly reactive. But Upendra
Drahal (Amgen) noted that sotorasib has only weak affinity (Ki = 86 µM)
but a high kinact (0.85 s-1) for the G12C mutant form of
KRAS, despite being quite stable against glutathione. High reactivity is fine,
as long as it is highly selective reactivity.
Jeffrey Martin (Biogen) spoke
about covalent fragments applied to neuroscience, including targets for Alzheimer’s
(tau) and Huntington’s disease. And in two separate talks Dan Nomura (UC Berkeley)
provided numerous examples of finding covalent fragments against a variety of
targets, including cMYC and E3 ligases (more on those below).
Keynote speaker Michelle Arkin
(UCSF) described using disulfide Tethering to find reversible covalent binders
of caspase 6 that were subsequently optimized to cell-active irreversible
inhibitors. She provided an evocative visual metaphor of proteins participating
in an English country dance, moving from partner to partner in a dynamic yet choreographed
fashion. The most popular dancers are the 14-3-3 proteins, which act as hubs mediating
binding to hundreds of other proteins. Michelle has found stabilizers of some
of these interactions, which could shut down aberrant disease signaling.
Covalent ligand discovery is best
done with mass spectrometry, and two talks revealed useful new methods. Jim
Nonomiya described an approach he and his Genentech colleagues developed called
CoMPAS, covalent mapping by peptide attenuation screening. This method uses an
isotopically labeled peptide as an internal standard to assess disappearance of
covalently modified peptides from enzymatically digested proteins. Sensitivity
can be much better than for intact protein mass spectrometry, allowing lower
consumption of scarce recombinant protein. Depending on the type of setup,
throughput can also be higher.
Throughput is the name of the
game in a method presented by Nate Elsen (AbbVie) called IR-MALDESI-MS. The home-built
system uses a laser to gently ionize aqueous solutions in 384-well plates
before running them through an electrospray mass spectrometer. The system can
analyze up to 20 samples per second, including intact proteins.
Non-covalent fragments
Turning to non-covalent methods, Rod
Hubbard (Vernalis) provided an update of the PAC-FragmentDEL approach which we highlighted last year. DNA-encoded libraries can be mind-bogglingly large, with more than a
trillion molecules at Hitgen. The fragment set is much smaller, at just 130,000
members, but this is still two orders of magnitude larger than a typical fragment
library. (Speaking of which, please make sure to fill out our library survey on
the right-hand side of the screen if you haven’t already done so.) This
increased chemical diversity increases the odds of finding rare molecules, such
as molecular glues that bind to protein complexes rather than individual
components.
Success stories are always
plentiful at conferences. Timo Heinrich (EMD Serono) described using SPR to
identify fragments that were optimized to orally bioavailable inhibitors of the
anti-cancer target TEAD1, which we wrote about here. Mihir Mandal (Merck)
described the use of fragment concepts in the development of clinical
candidates targeting metallo-β-lactamases, an important cause of antibiotic
resistance. Chris Smith described Mirati’s discovery of inhibitors against the
anti-cancer target PRMT5/MTA, one of which has gone into the clinic (see here
and here). And Tanweer Khan traced the origins of renin and plasmepsin
inhibitors to work on the aspartyl protease BACE1 at Merck, which we wrote about
here.
Sometimes we learn just as much from
projects that don’t move forward, as illustrated in a nice talk by Haihong Wu.
He and his AbbVie colleagues were interested in the tau protein, which is
intrinsically disordered, making structure-based design difficult. Although a two-dimensional
NMR screen identified several dozen fragment hits, these were hard to optimize,
with sharp, non-linear SAR. Perhaps the covalent binders we mentioned above will be more advanceable.
Targeted protein degradation
Targeted protein degradation and
induced proximity were major themes of the conference. We speculated several
years ago that FBLD could be useful here, and this has turned out to be
abundantly true.
E3 ligases attach ubiquitin to other
proteins, marking them for degradation. More than 600 exist in the human
genome, but only a handful have been co-opted for targeted protein degradation, and
everyone is racing to find new and better ligands for the unexplored E3 ligases.
Mary Matyskiela described how she and her colleagues at Neomorph are using
fragment screening to identify such ligands. She said they have been able to
use cryo-electron microscopy to guide structure-based design.
Dan Nomura’s second talk focused
on finding ligands against E3 ligases, including UBE2D and RNF126. For both of
these proteins small covalent ligands seem to be generally useful for causing
degradation of target proteins, and because the chemical structures have been
disclosed it will be fun to see them explored in more systems.
A significant focus for targeted
protein degradation is to find ligands for E3s that are restricted to specific
tissues or tumors. Steve Fesik (Vanderbilt) described using SAR by NMR to find
ligands against three E3 ligases, including one not expressed in the heart,
which could avoid cardiotoxicity. Steve also described using SAR by NMR to find
nanomolar binders for β-catenin. These are being used to make degraders for
this anti-cancer target.
Many of the molecules used for
targeted protein degradation are well beyond conventional rule-of-five space as
they contain binding moieties for the target of interest as well as an E3
ligase. Reflecting on his forty-year career as a medicinal chemist at Bristol
Myers Squibb, keynote speaker Nicholas Meanwell noted that a beautiful drug is
one that helps patients, not one that fits a set of metrics. For small molecule
therapeutics, he observed, “the opportunities have never looked better.”
We’ll end on this note, but
please feel free to leave comments about your highlights. And mark your
calendar for April 1-4, when DDC returns to San Diego.
4 comments:
Dan, I am always amazed at how you manage to succinctly describe the highlights of 4 days of talks and discussions, and yet leave us feeling that you captured it all.
Thanks for sharing your insights and appreciate all your contributions and efforts in helping us get the event to where it is today. 18 years and counting!
See you at Discovery on Target in Boston, in the Fall.
Any chance any of the TPD session speakers revealed what E3 ligases they are working on? :-)
Also, "tissue specific" based on RNA levels/transcriptomics, or real protein data?
Thanks Tanuja for the kind words and for organizing a great meeting!
GK, some of the speakers (Dan Nomura, Eric Fischer, Simon Bailey) did mention specific E3s, but as you might guess others were fairly cagey. Steve Fesik noted that finding tissue- or tumor-specific E3s was tough and that public data are not reliable.
Happy to see few talks on ligases beyond cereblon like KEAP1, DCAF1 etc. I am hoping we will have more coming to the forefront. Indeed tissue-specific targeting will be a key aspect going forward.
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