Scientific Impact
Therapeutic discovery rarely follows a straight line.
The Fisher Drug Discovery Resource Center contributes to research at many
different points in the discovery process. A project may begin with assay
development and chemical screening, with an existing compound that suggests a
new therapeutic opportunity, or with a specific experimental question within
a program already underway. As the science evolves, projects may move between
screening, medicinal chemistry, mechanistic studies, biophysical
characterization, and biological validation.
Several DDRC collaborations illustrate these different paths. Work with the
Tuschl laboratory
has included assay development and chemical screening directed toward new
therapeutic targets. Studies of cGAS produced small-molecule inhibitors,
publications, and intellectual property, while pharmacological inhibition of
cGAS has subsequently become an active area of therapeutic development. More
recently, collaboration with the Tuschl laboratory contributed to the discovery
of inhibitors of the SARS-CoV-2 NSP14 RNA cap methyltransferase, reported in
Nature.
Work with the
Buck-Levin laboratory
at Weill Cornell Medicine followed a similarly long trajectory. Assay
development and screening contributed to the discovery of LRE1, a selective
allosteric inhibitor of soluble adenylyl cyclase (sAC). What began as the
discovery of a chemical tool developed into a broader effort to
pharmacologically inhibit sAC, contributing to the exploration of sAC
inhibition as an approach to non-hormonal male contraception.
A collaboration with the
Bindra laboratory
followed a different route. Rather than beginning with the discovery of a new
chemical entity, the work explored drug repositioning for glioblastoma (GBM).
The resulting research progressed from preclinical investigation to clinical
evaluation, illustrating how screening and experimental drug discovery can
also uncover new therapeutic uses for existing compounds.
Collaboration with the
Vosshall laboratory
at Rockefeller produced another kind of outcome. Chemical screening identified
small-molecule agonists of an Aedes aegypti neuropeptide Y receptor
that suppressed mosquito host-seeking and biting behavior. The work connected
chemical discovery with mosquito sensory biology and suggested a new approach
to interfering with mosquito biting. Leslie Duvall, who led the study,
subsequently established her own laboratory at Columbia University, where the
biology of mosquito behavior continues to be investigated.
In other cases, the DDRC may contribute at a later stage of an established
therapeutic program. Work with the
Crystal laboratory
at Weill Cornell Medicine used quantitative surface plasmon resonance (SPR)
measurements to address a specific question within a therapeutic program
already underway. In this setting, the contribution was not an initial
screening hit, but quantitative biophysical evidence needed as the program
developed.
The history of the Center also demonstrates how far an early discovery can
travel. Work with the
Coller laboratory
began with high-throughput screening for small-molecule inhibitors of the
platelet integrin αIIbβ3. The initial RUC series provided a starting point for
years of subsequent medicinal chemistry and structure-guided optimization,
ultimately leading to zalunfiban, an investigational antiplatelet agent
developed for the early treatment of acute myocardial infarction. This work
began at the Center before its current directorship and illustrates the long
time horizon over which the impact of an early discovery may emerge.
Together, these examples illustrate the varied and often iterative nature of
drug discovery. A screening hit may become the starting point for years of
subsequent work. An existing drug may acquire a new therapeutic purpose. An
unexpected screening result may open a new biological direction. A quantitative
measurement may help answer an important question within an established
program. The DDRC supports these different paths by bringing together
scientific expertise, chemical resources, screening technologies, quantitative
measurements, and data analysis as the needs of a project evolve.
Selected Discoveries
Targeting an essential SARS-CoV-2 enzyme
A collaborative antiviral discovery program identified small-molecule
inhibitors of the SARS-CoV-2 NSP14 RNA cap methyltransferase, an enzyme involved
in viral RNA processing. The work established NSP14 as a chemically tractable
antiviral target and identified compounds capable of inhibiting viral
replication.
Meyer C, Garzia A, Miller MW, et al. Small-molecule inhibition of
SARS-CoV-2 NSP14 RNA cap methyltransferase. Nature. 2025;637:1178-1185.
View publication
Small-molecule inhibitors of human cGAS
Small-molecule inhibitors were developed against human cyclic GMP-AMP synthase
(cGAS), a key sensor of cytosolic DNA. The study provided chemical tools for
suppressing dsDNA-triggered interferon signaling and established a foundation
for continued pharmacological investigation of this innate immune pathway.
Lama L, Adura C, Xie W, et al. Development of human cGAS-specific
small-molecule inhibitors for repression of dsDNA-triggered interferon
expression. Nature Communications. 2019;10:2261.
View publication
Using chemical biology to block mosquito biting
A chemical screen identified small-molecule agonists of an
Aedes aegypti neuropeptide Y receptor that suppress mosquito
host-seeking and biting behavior. The work connected chemical screening with
mosquito sensory biology and suggested a potential new strategy for controlling
interactions between mosquitoes and human hosts.
Duvall LB, Ramos-Espiritu L, Barsoum KE, Glickman JF, Vosshall LB.
Small-Molecule Agonists of Ae. aegypti Neuropeptide Y Receptor Block Mosquito
Biting. Cell. 2019;176:687-701.e5.
View publication
Discovery of an allosteric inhibitor of soluble adenylyl cyclase
Screening and follow-up studies led to the discovery of LRE1, a selective
allosteric inhibitor of soluble adenylyl cyclase (sAC). The compound provided
a new chemical tool for studying sAC-dependent signaling and became a starting
point for continued efforts to pharmacologically inhibit sAC.
Ramos-Espiritu L, Kleinboelting S, Navarrete FA, et al. Discovery of LRE1
as a specific and allosteric inhibitor of soluble adenylyl cyclase.
Nature Chemical Biology. 2016;12:838-844.
View publication
Targeting the Aβ-fibrinogen interaction in Alzheimer’s disease
A small-molecule approach was used to disrupt the interaction between amyloid-β
and fibrinogen, linking chemical discovery with a mechanism connecting vascular
dysfunction and Alzheimer’s disease. In mouse models, inhibition of this
interaction improved abnormal thrombosis and cognitive outcomes.
Ahn HJ, Glickman JF, Poon KL, et al. A novel Aβ-fibrinogen interaction
inhibitor rescues altered thrombosis and cognitive decline in Alzheimer’s
disease mice. Journal of Experimental Medicine. 2014;211:1049-1062.
View publication
Blocking Sonic Hedgehog signaling through Hedgehog acyltransferase
Small-molecule inhibitors of Hedgehog acyltransferase were identified and shown
to inhibit Sonic Hedgehog signaling. The work demonstrated that targeting the
lipid modification of a signaling protein could provide a chemical strategy
for modulating Hedgehog pathway activity.
Petrova E, Rios-Esteves J, Ouerfelli O, Glickman JF, Resh MD.
Inhibitors of Hedgehog acyltransferase block Sonic Hedgehog signaling.
Nature Chemical Biology. 2013;9:247-249.
View publication
Publications
DDRC-supported research has contributed to publications spanning drug
discovery, chemical biology, infectious disease, neuroscience, cell biology,
and other areas of biomedical research.
The complete collection includes studies involving scientific collaboration
with DDRC staff as well as research using Center instrumentation, compound
libraries, screening infrastructure, and other resources.