title: 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.
abstract: We 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 G(1) 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.
authors.affiliation: Maxim Pharmaceuticals Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Han-Zhong
authors.initials: HZ
authors.lastname: Zhang
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Jared
authors.initials: J
authors.lastname: Kuemmerle
authors.forename: William
authors.initials: W
authors.lastname: Kemnitzer
authors.forename: Kristin
authors.initials: K
authors.lastname: Ollis-Mason
authors.forename: Ling
authors.initials: L
authors.lastname: Qiu
authors.forename: Candace
authors.initials: C
authors.lastname: Crogan-Grundy
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000070796:Perilipin-3; D011257:Pregnancy Proteins / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D033921:Vesicular Transport Proteins
chemical_list: C503899:5-(3-chlorothiophen-2-yl)-3-(5-chloropyridin-2-yl)-1,2,4-oxadiazole; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010069:Oxadiazoles; C038196:PLIN3 protein, human; D000070796:Perilipin-3; D011257:Pregnancy Proteins; D017527:Receptor, IGF Type 2; D013876:Thiophenes; D033921:Vesicular Transport Proteins; D020169:Caspases