Assay and Drug Development Technologies - 2

approach] integrates matured technologies such as chemical
biology, structural biology, cryo-electron microscopy, and
proteomics,'' Glucksmann notes. ''This allows us to pursue
targets that were deemed undruggable.''
While Cedilla is focused on precision oncology with a
number ofprograms in the preclinical stage, Glucksmann feels
that this strategy ultimately has many other applications.
''This is not a shotgun approach,'' she insists. ''Rather, it is a
target-centric pursuit.''
Cedilla Therapeutics believes that drug discovery should account
for the functional states of target proteins. When the company
characterizes native, full-length proteins, it considers posttranslational
modifications, protein-protein interactions, and subcellular
localization. This approach has helped the company develop
conditional inhibitors that unlock critical and elusive cancer
targets including TEAD and CDK2.
The company is also targeting proteins that form complexes.
''We are developing small molecules that selectively
bind the cyclin-dependent kinase 2 (CDK2)/cyclin E complex,''
Glucksmann elaborates. ''We have developed an inhibitor
with exquisite selectivity that is likely to translate
into a better safety profile as compared to traditional kinase
inhibitors.''
The key to the company's approach is to find a validated
target and develop drugs using a holistic approach. ''[Such an
3D CELLULAR MODELS
Traditionally, once a potential drug candidate is identified,
the compound is tested for efficacy and toxicity in twodimensional
(2D) cell cultures and animal models. According
to Rosha Poudyal, PhD, science and technology advisor, 10x
Genomics, 2D models present significant challenges for drug
discovery. ''They lack cellular heterogeneity, cell-to-cell interactions,
and the ability to recapitulate the tissue microenvironment
found in vivo,'' she details. ''Similarly, drugs that
are successful in animal models can fail in the clinical phase
because of reproducibility issues that are due to genetic differences
between animal models and humans.''
Poudyal suggests that some of the challenges encountered
with 2D models can be avoided iforganoid models are used in
concert with single-cell and spatial solutions. ''Organoid
models are tiny, self-organizing, in vitro 3D cellular models,''
she explains. ''They exhibit heterogeneous cellular composition
and mimic the physiology of the organ in vivo, providing
a platform to study human physiology that might be difficult
to recapitulate in animal models. Organoids can be used for
target identification, high-throughput drug screening, drug
efficacy, and toxicity studies, and they have the potential to
link preclinical and clinical data.''
When organoids are used in combination with single-cell
technology to assess drug responses, researchers can assess
cell-to-cell heterogeneity, understand gene regulatory networks,
and perform pathway analysis. ''Furthermore,''
Poudyal adds, ''single-cell resolution allows the identification
of subpopulations of cells that are not as responsive or are
resistant to the drug application.''
Poudyal says that these kinds of studies can be performed
Confo Therapeutics has developed ConfoBodies to drive drug
discovery. A ConfoBody is a single-domain antibody (VHH) that can
bind to a protein or protein complex when it is in a therapeutically
relevant conformation. For example, a ConfoBody can be used to
stabilize a target in its agonist-bound active state. This image
shows a ConfoBody stabilizing the active form of a GPCR-G-protein
complex to facilitate the discovery of a new GPCR-targeted drug,
the ''Ago VHH.''
with patient-derived tumor organoids: ''These models are
gaining traction in precision medicine. They can be used in
screening applications to identify drug(s) that would provide
the most benefit to the individual patient. Similarly, neural
organoids provide a platform to model neurodegenerative
diseases, such as Alzheimer's disease, where many therapies
have been successful in animal models but have failed to get
approved for clinical use.''
2 Genetic Engineering & Biotechnology News
ª 2022 GEN PUBLISHING
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