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

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

  • J Lipid Res. 2016 Mar;57(3):368-79. doi: 10.1194/jlr.M062794.
Ke Liu 1 Naoko Kunii 1 Megumi Sakuma 2 Atsumi Yamaki 1 Satoru Mizuno 1 Mayu Sato 1 Hiromichi Sakai 1 Sayaka Kado 3 Kazuo Kumagai 4 Hirotatsu Kojima 4 Takayoshi Okabe 4 Tetsuo Nagano 4 Yasuhito Shirai 2 Fumio Sakane 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Chiba University, Chiba 263-8522, Japan.
  • 2 Department of Applied Chemistry in Bioscience, Graduate School of Agricultural Science, Kobe University, Kobe 657-8501, Japan.
  • 3 Graduate School of Science and Center for Analytical Instrumentation, Chiba University, Chiba 263-8522, Japan.
  • 4 Drug Discovery Initiative, University of Tokyo, Tokyo 113-0033, Japan.
  • 5 Department of Chemistry, Chiba University, Chiba 263-8522, Japan sakane@faculty.chiba-u.jp.
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.

Keywords

T cell; anergy; anticancer drug; apoptosis; cancer; high-throughput screening; interleukin-2; lipid kinases; phosphatidic acid.

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