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Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2)
Zhonghua Pei ,
Rohan Mendonca ,
Lewis Gazzard ,
Richard Pastor ,
Leanne Goon ,
Amy Gustafson ,
Erica VanderPorten ,
Georgia Hatzivassiliou ,
Kevin Dement ,
Robert Cass ,
Po-wai Yuen
1 ,
Yamin Zhang
1 ,
Guosheng Wu
1 ,
Xingyu Lin
1 ,
Yichin Liu ,
Benjamin D. Sellers
April 24 2018
April 02 2018
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Abstract
<p class="first" id="d3382941e265">
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<img alt="" class="figure" src="/document_file/eb0d1a69-9ff0-4389-8758-d4a93dde7fe5/PubMedCentral/image/ml-2017-004277_0008"/>
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</p><p id="d3382941e269">Tryptophan
2,3-dioxygenase 2 (TDO2) catalyzes the conversion of
tryptophan to the immunosuppressive metabolite kynurenine. TDO2 overexpression
has been observed in a number of cancers; therefore, TDO inhibition
may be a useful therapeutic intervention for cancers. We identified
an aminoisoxazole series as potent TDO2 inhibitors from a high-throughput
screen (HTS). An extensive medicinal chemistry effort revealed that
both the amino group and the isoxazole moiety are important for TDO2
inhibitory activity. Computational modeling yielded a binding hypothesis
and provided insight into the observed structure–activity relationships.
The optimized compound
<b>21</b> is a potent TDO2 inhibitor
with modest selectivity over indolamine 2,3-dioxygenase 1 (IDO1) and
with improved human whole blood stability.
</p>