Assay and Drug Development Technologies - 1

DRUG DISCOVERY
Drug Discovery Picks Up the Pace, Stays on Target
Kathy Liszewski
Conditional modulation of proteins, 3D cell models, GPCRstabilizing
technology, and novel mRNA instrumentation promise
to speed drug discovery in 2022 and beyond.
Several new technologies that are being used to accelerate
drug discovery are highlighted in this article. They include small
molecules that conditionally modulate proteins in their functional
state; three-dimensional (3D) cell models, or organoid
models, that assist with target identification, high-throughput
drug screening, drug efficacy analyses, and toxicity studies;
technologies that stabilize G protein-coupled receptors (GPCRs)
to enable the discovery of agonistic biologics; and automated
instrumentation that enables the overnight synthesis ofmRNA.
DRUGGING THE ''UNDRUGGABLE''
''While about 50% of the proteome
plays a role in human disease, only 10%
is accessible to conventional therapeutics,''
says Alexandra Glucksmann,
PhD, president and CEO, Cedilla Therapeutics.
To overcome that challenge,
the company is pursuing a ''target
According to scientists at 10x Genomics, drug developers can benefit
from combining two powerful technologies: three-dimensional cell
culture and single-cell analysis. The company's single-cell and spatial
solutions may be particularly apt given that organoid models have
been shown to capture someof the cellular heterogeneity observed in
patient tissues. By combining organoids and single-cell assays, drug
developers may improve their target identification, high-throughput
drug screening, drug efficacy, and drug toxicity studies.
V
oltaire argued, ''Perfection is attained by slow degrees;
it requires the hand of time.'' However, in
drug discovery projects, perfection can't be attained
soon enough. A project to develop a perfect drug, or
a drug that is as safe and effective as possible, may never begin
if it can't be completed quickly. Such predicaments must have
been familiar to the philosopher. After all, he also complained
that the perfect is the enemy of the good.
If only Voltaire were here today to see how drug discovery is
being accelerated by new technologies. He might reverse himself
and declare that the perfect can in fact be the friend ofthe good.
Reprinted with permission from Genet Eng Biotechnol News 2022;42(1):46-50.
Alexandra Glucksmann,
PhD,PresidentandCEO,
Cedilla Therapeutics.
centric'' approach to drug discovery.
''We are developing small molecules
that conditionally modulate proteins in
their functional state,'' Glucksmann
explains. Such molecules, she continues,
may provide ''unprecedented precision
therapeutics.''
According to Glucksmann, to access traditionally undruggable
targets, it's critical to understand the importance of
form and context of targets in their natural settings: ''We are
bringing forward a new dimension in precision oncology by
selectively inhibiting oncogenic drivers using small molecules
that inhibit proteins in their functional states.''
Sincemuch ofthe distinctiveness ofproteins depends on posttranslational
modifications, Glucksmann suggests that when
active sites are targeted, focusing on post-translational modifications
can be effective. For example, solid tumors such as
mesothelioma and certain types ofsquamous cell cancers feature
a dysregulated key component of the Hippo signaling pathway
called TEAD (transcriptional enhanced association domain). The
aberrant regulation of this nuclear transcription factor is increasingly
implicated in resistance to targeted therapies.
''The palmitoylation of TEAD is critical for its stability and
function,'' Glucksmann points out. ''Through genetic screens,
we identified a very selective molecule that inhibits the
function of TEAD by binding to this specific pocket.''
DOI: 10.1089/gen.42.01.15
ª 2022 GEN PUBLISHING Genetic Engineering & Biotechnology News 1
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