A novel diacylglycerol kinase α-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response.

Journal of Lipid Research
Ke LiuFumio Sakane

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 c...Continue Reading

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Citations

Sep 2, 2016·Frontiers in Cell and Developmental Biology·Fumio SakaneSuguru Komenoi
Nov 2, 2016·Frontiers in Cell and Developmental Biology·Matthew J RieseSteven M Albelda
Nov 3, 2016·Frontiers in Cell and Developmental Biology·Richard M EpandMathieu Lemaire
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Jan 18, 2019·Protein Science : a Publication of the Protein Society·Daisuke TakahashiFumio Sakane
Feb 5, 2019·Journal of Biochemistry·Daiki HayashiYasuhito Shirai
Nov 24, 2019·International Journal of Molecular Sciences·Poojitha SitaramMatthew J Riese
Jul 2, 2020·Clinical Science·Gianluca BaldanziMario Malerba
Nov 27, 2019·International Journal of Molecular Sciences·Gianluca Baldanzi, Mario Malerba
Sep 24, 2020·International Journal of Molecular Sciences·Jae Ang SimDongki Yang
Nov 7, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Suresh VelnatiGianluca Baldanzi
Jul 30, 2020·International Journal of Molecular Sciences·Antonietta FazioStefano Ratti
Sep 20, 2020·International Journal of Molecular Sciences·Fumio SakaneChiaki Murakami
Oct 13, 2020·Frontiers in Cell and Developmental Biology·Mikel M Arbulo-EchevarriaEnrique Aguado
Jan 6, 2019·European Journal of Medicinal Chemistry·Suresh VelnatiGianluca Baldanzi
Jul 25, 2019·Trends in Endocrinology and Metabolism : TEM·Julie Massart, Juleen R Zierath
Nov 11, 2019·Advances in Biological Regulation·Javier Arranz-Nicolás, Isabel Mérida
Jan 9, 2021·Cancer & Metabolism·Shilpa R NagarajanAndrew J Hoy
Mar 19, 2020·Biochemical and Biophysical Research Communications·Yuki MurakamiFumio Sakane
Aug 25, 2020·Current Opinion in Pharmacology·Taku Kambayashi, Deepak A Deshpande
Jun 3, 2021·International Journal of Molecular Sciences·Suresh VelnatiGianluca Baldanzi
Nov 11, 2021·Pharmaceutical Patent Analyst·Hermann Am Mucke

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