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Discovery and Structure−Activity Relationship of 3-Aryl-5-aryl-1,2,4-oxadiazoles as a New Series of Apoptosis Inducers and Potential Anticancer Agents
journal contribution
posted on 2005-08-11, 00:00 authored by Han-Zhong Zhang, Shailaja Kasibhatla, Jared Kuemmerle, William Kemnitzer, Kristin Ollis-Mason, Ling Qiu, Candace Crogan-Grundy, Ben Tseng, John Drewe, Sui Xiong CaiWe have identified 5-(3-chlorothiophen-2-yl)-3-(4-trifluoromethylphenyl)-1,2,4-oxadiazole (1d)
as a novel apoptosis inducer through our caspase- and cell-based high-throughput screening
assay. Compound 1d has good activity against several breast and colorectal cancer cell lines
but is inactive against several other cancer cell lines. In a flow cytometry assay, treatment of
T47D cells with 1d resulted in arrest of cells in the G1 phase, followed by induction of apoptosis.
SAR studies of 1d showed that the 3-phenyl group can be replaced by a pyridyl group, and a
substituted five-member ring in the 5-position is important for activity. 5-(3-Chlorothiophen-2-yl)-3-(5-chloropyridin-2-yl)-1,2,4-oxadiazole (4l) has been found to have in vivo activity in a
MX-1 tumor model. Using a photoaffinity agent, the molecular target has been identified as
TIP47, an IGF II receptor binding protein. Therefore, our cell-based chemical genetics approach
for the discovery of apoptosis inducers can identify potential anticancer agents as well as their
molecular targets.
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flow cytometry assay4 lG 1 phasePotential Anticancer AgentsCompound 1MXT 47D cellscancer cell linesApoptosis Inducersvivo activityIGF II receptor binding proteinanticancer agentspyridyl groupapoptosis inducersnovel apoptosis inducerSAR studiescolorectal cancer cell linesphotoaffinity agentNew Seriestumor model
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