Cambridge Healthtech Institute
held its annual Discovery on Target (DoT) meeting in Boston last week. Attendance
may have set a record, with over 1000 participants. There were sessions on antibodies,
conjugates, and radioligands, but I’ll just touch on some of the small molecule
themes most relevant to this blog.
Covalent approaches
As with last year, covalent
approaches to drug discovery were well-represented. Dhirendra Simanshu
(Frederick National Laboratory) described several drugs birthed in the NCI RAS Initiative,
including ones targeting the G12C mutant of KRAS and C242 on the RAS-binding
domain of PI3Kα. He also
described how various KRAS mutants cause resistance to drugs, finding that most
of them affect the KI term (binding) more than the kinact
term (bonding). Continuing on the KRAS theme, Jack Sloan discussed efforts at
BMS to discover inhibitors targeting both the on- and off-states of KRAS G12C.
Kasia Handing (Tango
Therapeutics) presented both covalent and non-covalent approaches against VRK1,
a synthetic lethal target for glioblastoma. A biochemical screen yielded
covalent inhibitors that were characterized crystallographically, but they
turned out to be too non-selective to progress. In the meantime, an in-cell
DNA-encoded library (DEL) screen led to more advanceable molecules.
DEL was indeed a major topic of
the conference, and here too covalent approaches are being explored. Elizabeth D’ambrosio
described how GSK is identifying covalent binders from DEL screens, a process which
includes testing for time-dependence as well as aggressive washing steps under
denaturing conditions to quench unreacted molecules and wash away any sticky,
non-covalently bound compounds. And Xiaojie Bruce Lu (Chinese Academy of
Sciences) described applying DEL to a variety of targets, including some
covalently targeting non-cysteine residues.
One of the advantages of DEL is
being able to screen large libraries, and increasing throughput is also of
interest to Harvard’s Steve Gygi, who is screening covalent fragments against
cells and cell lysates. In 2024 we described how he was using tandem mass tag
(TMT) multiplexing to analyze 18 samples in a single mass-spectrometry run, and
he has now extended this to 35 samples. What’s more, Steve is combining 16
different fragments in each sample and introducing clever deconvolution
approaches to further accelerate the process.
Not everyone is targeting
cysteine residues. Mark Tye described the discovery of Revolution Medicines’
zoldonrasib, which uses an aziridine warhead to target the G12D mutant of KRAS.
And Balyn Zaro (University of California San Francisco) described using
ninhydrin derivatives to target arginine. Most organic chemists are familiar
with ninhydrin’s reaction with primary amines such as the N-termini of peptides,
but Balyn has been able to optimize selectivity for arginine and has used the
resulting chemical probes to identify more than 7000 arginine residues in
cells, about 5% of which are hyperreactive. Interestingly, some cell lines seem
to have a greater proportion of reactive arginine residues than others.
Direct-to-Biology (D2B)
approaches
Another recurring theme was
direct-to-biology, in which crude reaction mixtures are screened directly in
various assays without purification. Indeed, Nicholas Bland of Domainex said
that after looking at the agenda of the meeting he considered skipping the
introductory slides – and this was on the first official day of the conference.
Nicholas described using D2B for optimizing PROTACs as well as for improving
fragment hits against the GPCR A2A receptor.
Jack Sadowsky, who also presented
at DDC this past spring, described how he and his colleagues at Kimia are using
D2B in combination with machine learning to develop selective inhibitors of
kinases while also improving their in vitro ADME properties. This effort
entailed making and testing tens of thousands of compounds from a virtual space
of some 80 million molecules.
But even small-scale D2B can be
valuable. Trevor Sherwood described how he and his colleagues at BMS used D2B
to make and test 663 molecules to improve the potency of an EP4 agonist
identified from a high-throughput screen. This involved multiple reaction
types, including photoredox chemistry, for which they built a custom-designed
reactor to evenly heat and illuminate the microtiter plates. The D2B work was
done in parallel with medicinal chemistry, but interestingly the development
candidate BMS-986526 came directly from the D2B work and has entered a phase 1/2a trial for rheumatoid arthritis.
There were other talks and
posters on D2B that I missed, but I did attend two breakfast roundtables on the
topic that were quite lively despite happening at 7:30 – a testament to
the interest in the topic.
“Traditional” fragment-based
drug discovery
At a plenary panel moderated by
Drug Hunter’s Dennis Hu on drugging difficult targets, Biogen’s Klaus Urbahns
asked the other panelists if they were still doing fragment-based lead
discovery. John Tallarico of Novartis and Ian Storer of AstraZeneca immediately
said yes. And in a separate presentation, Kris Borzilleri described how she and
her Pfizer colleagues used fluorine-detected NMR and fragment optimization to
identify ligands for an orphan GPCR.
Debanu Das described using
high-throughput crystallography screening at XPose Therapeutics, now part of
Mid-Atlantic BioTherapeutics, to identify inhibitors of DNA damage response
pathway proteins. Although the initial hits had no detectable activity, SAR by
catalog was able to get to nanomolar inhibitors of the protein APE1, which is
overexpressed in ovarian cancer, in a matter of weeks.
But perhaps the most robust validation
of FBDD was provided by Steve Fesik of Vanderbilt, who described a decades-long
effort to drug the MYC pathway, which is probably dysregulated in almost all cancers.
We described some of his published work on WDR5 here, but he is now making
progress against MYC itself. This has not been easy: MYC is intrinsically
disordered, and SAR-by-NMR screens against both the transactivation domain and
the DNA-binding domain failed. However, MYC forms a structured leucine-zipper
heterodimer with the protein MAX, and screening this complex yielded hits at
the DNA binding interface. (Earlier this year we described work from Novartis on a
different leucine zipper.) The hits have been optimized to low nanomolar
binders that disrupt DNA binding, unlike a slide full of other (alleged) MYC
inhibitors, including high-profile commercially available compounds such as
MYCi361 and MYCi975.
I’ll close – hopefully before you
stop reading. If you attended, what talks or posters stood out? And if you wish
you had attended, mark your calendar for Oct. 18-21 next year, when DoT returns
to Boston in time for peak leaf-peeping season.
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