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Investigator : Young-Tae Chang, Ph.D
Department of Chemistry, New York University, New York, New York 10016
Background
Cancers are the leading cause of death among humans. Current chemotherapeutics and
radiation therapies are targeted towards inducing DNA damage that indiscriminately
kills cells, with the hope that cancerous cells will die more rapidly than healthy
cells. Unfortunately, these treatments are often not effective and are associated
with severe side effects resulting in prolonged suffering for the patient.
Microtubules are an array of fibrous cytoskeletal proteins that are essential for
the actual separation and division of cellular components and distribution of DNA
during mitosis. Interruption of this process can halt cell division without any inherent
cytotoxic effects. Several tubulin-binding drugs such as colchinines and taxols have
shown promise as potential anti-cancer drugs. However, problems with inherent toxicity,
low solubility of the drug, availability in quantity, and multi-drug resistance still
exist. As most of the lead compounds originated from naturally occurring sources,
an alternative approach may involve screening of small synthetic molecules for tubulin-binding
compounds. Myoseverin, a recently discovered small-molecule tubulin-binder has demonstrated
a promising ability to surmount the major problems associated with currently available
tubulin-binding drugs. Nevertheless problems with low-level activity and activation
of biochemical pathways involved with wound healing remain unresolved. These findings
indicate that high-throughput screening of small-molecule libraries is an attractive
approach to identifying novel anti-cancer therapeutics.
Description of project
Triazines, which are structurally similar to purines or pyrimidines, are attractive
therapeutics because of their small molecular size and highly flexible scaffold.
Furthermore, the starting materials and all the required building blocks are relatively
inexpensive. For these reasons, triazine has elicited significant interest as an
ideal scaffold for potential combinatorial libraries.
The present invention describes the creation of a triazine library using a proprietary
synthetic pathway that allows for a more diverse library. Further, the addition of
linkers that immobilize the small molecules so that potential target proteins may
be screened is performed using a novel approach that saves weeks or months compared
to previous methods.
The combination of these technologies will permit us to construct the first small
molecule library chips. Thousands of triazine molecules can be immobilized on glass
slides, which will subsequently be incubated with fluorescence labeled proteins with
different dyes. Analyses of the color by scanner will directly give the absolute
and relative binding affinity of different proteins on each compound. With this technique,
thousands of small molecule drug candidates can be tested using small amounts of
proteins.
Application
The triazine small molecule library can be utilized to create small molecule chips
that can be applied to many phenotypic assays. These high-throughput screens will
allow for expedient identification of proteins that may serve as potential targets
for small-molecule drugs. Here, we discuss the potential of finding anti-cancer therapeutics;
however, we believe that the described invention has a far-reaching potential and
that the powerful technique will revolutionize genome-wide study by opening a new
field of “chemical proteomics”. During the procedure of the invention,
novel protein targets and their small molecule drug candidates may be found for a
wide range of diseases.
Patents
Patents covering this technology have been filed.
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