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.
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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.
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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.
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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.
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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.
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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.
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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.