title: A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response.
abstract: Diacylglycerol kinase (DGK) consists of 10 isozymes. The α-isozyme enhances the proliferation of cancer cells. However, DGKα facilitates the nonresponsive state of immunity known as T-cell anergy; therefore, DGKα enhances malignant traits and suppresses immune surveillance. The aim of this study was to identify a novel small molecule that selectively and potently inhibits DGKα activity. We screened a library containing 9,600 chemical compounds using a newly established high-throughput DGK assay. As a result, we have obtained a promising compound, 5-[(2E)-3-(2-furyl)prop-2-enylidene]-3-[(phenylsulfonyl)amino]2-thioxo-1,3-thiazolidin-4-one) (CU-3), which selectively inhibited DGKα with an IC50 value of 0.6 μM. CU-3 targeted the catalytic region, but not the regulatory region, of DGKα. CU-3 competitively reduced the affinity of DGKα for ATP, but not diacylglycerol or phosphatidylserine. Moreover, this compound induced apoptosis in HepG2 hepatocellular carcinoma and HeLa cervical cancer cells while simultaneously enhancing the interleukin-2 production of Jurkat T cells. Taken together, these results indicate that CU-3 is a selective and potent inhibitor for DGKα and can be an ideal anticancer drug candidate that attenuates cancer cell proliferation and simultaneously enhances immune responses including anticancer immunity.
authors.affiliation: Department of Chemistry, Chiba University, Chiba 263-8522, Japan.
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Chiba University, Chiba 263-8522, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kunii
authors.affiliation: Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Sakuma
authors.affiliation: Department of Chemistry, Chiba University, Chiba 263-8522, Japan.
authors.forename: Atsumi
authors.initials: A
authors.lastname: Yamaki
authors.affiliation: Department of Chemistry, Chiba University, Chiba 263-8522, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Department of Chemistry, Chiba University, Chiba 263-8522, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Chemistry, Chiba University, Chiba 263-8522, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Graduate School of Science and Center for Analytical Instrumentation, Chiba University, Chiba 263-8522, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kado
authors.affiliation: Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hirotatsu
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Okabe
authors.affiliation: Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.affiliation: Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Shirai
authors.affiliation: Department of Chemistry, Chiba University, Chiba 263-8522, Japan sakane@faculty.chiba-u.jp.
authors.forename: Fumio
authors.initials: F
authors.lastname: Sakane
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D019852:Diacylglycerol Kinase / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007376:Interleukin-2 / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation / Q000187:drug effects; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C000612427:5-(3-(2-furyl)prop-2-enylidene)-3-((phenylsulfonyl)amino)-2-thioxo-1,3-thiazolidin-4-one; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007376:Interleukin-2; D007527:Isoenzymes; D013449:Sulfonamides; D013844:Thiazoles; D012236:Rhodanine; D019852:Diacylglycerol Kinase
keywords: T cell; anergy; anticancer drug; apoptosis; cancer; high-throughput screening; interleukin-2; lipid kinases; phosphatidic acid