| dc.description.abstract |
<p>Cancer is one of the most devastating diseases in modern society, with over 1.6
million new cancer cases occurring in the US alone each year. DNA-damaging agents
are often the first line of defense against rapidly dividing cancer cells. However,
cancer cells can become resistant to chemotherapy by up-regulating an error-prone
DNA-repair process called translesion DNA synthesis (TLS). The Rev1 polymerase orchestrates
this pathway by recruiting one of three inserter polymerases and the extender polymerase
(Pol ζ) to bypass the lesion. Here we report the discovery and characterization of
an inhibitor of the protein-protein interaction between Rev1 and Rev7, a subunit of
Pol ζ, using biochemical and biophysical techniques. Our X-ray crystallographic structural
analysis of the Rev1 and the inhibitor (JH-RE-06) complex reveals that the inhibitor
blocks Rev7 binding by inducing Rev1 dimerization. Such an unexpected observation
is confirmed by an in vitro crosslinking assay. In vitro cell-killing assays show
that JH-RE-06 enhances sensitivity of a variety of cancer cell lines to a wide range
of chemotherapeutic agents; furthermore, co-administration of JH-RE-06 with cisplatin
significantly suppresses melanoma growth in mice and prolongs the survival time of
tumor bearing mice, highlighting the therapeutic potential of translesion synthesis
inhibitors as a novel class of cancer adjuvant therapeutics to enhance the outcome
of chemotherapy currently available to cancer patients.</p><p>Due to their compromised
immune systems, cancer patients are particularly susceptible to opportunistic bacterial
infections, many of which are becoming rapidly resistant to current antibiotic therapies.
We describe the combined use of X-ray crystallography and NMR spectroscopy to delineate
a cryptic inhibitor envelope for optimization of a small molecule inhibitor of LpxC,
an enzyme essential to the survival of Gram-negative bacteria. The resulting inhibitor
shows vast improvement over its parent compound over a wide range of bacterial orthologs.
</p><p>In summary, we demonstrate successful structural characterization and structure-guided
design and optimization of lead compounds in two different systems. These studies
have profound implications for drug discovery and lead optimization in other disease-relevant
systems as well.</p>
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