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

Liu, Ke; Kunii, Naoko; Sakuma, Megumi; Yamaki, Atsumi; Mizuno, Seitoku; Sato, Mayu; Sakai, Hiromichi; Kado, Satoshi; Kumagai, Kazuo; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo; Shirai, Yasuhito; Sakane, Fumio

doi:10.1194/jlr.m062794

Cited by 63 publications

(115 citation statements)

References 67 publications

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“…Probably the most robust method for detecting such changes is by using mass spectrometry. However, this has proven to be difficult without genetic manipulations [8,12,43]. Using LC-MS, we analyzed changes in DAG, PA and PC in cells expressing endogenous DGKs after treatment with ritanserin and R59022 but could not obtain statistically significant results.…”

Section: Resultsmentioning

confidence: 99%

“…Currently available chemical tools for understanding the role of DGKs in biology and disease are confined to the two long-known inhibitors, R59022 and R59949 (DGK inhibitor I and II, respectively) [10,11]. Very recently, another small molecule, CU-3, was identified as a novel DGKα inhibitor in vitro [12]. The selectivity of R59022 and R59949 for the different DGK isotypes has been debated.…”

Section: Introductionmentioning

confidence: 99%

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Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Boroda

Niccum

Raje

et al. 2017

Biochemical Pharmacology

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Diacylglycerol kinase alpha (DGKα) catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). Recently, DGKα was identified as a therapeutic target in various cancers, as well as in immunotherapy. Application of small-molecule DGK inhibitors, R59022 and R59949, induces cancer cell death in vitro and in vivo. The pharmacokinetics of these compounds in mice, however, are poor. Thus, there is a need to discover additional DGK inhibitors not only to validate these enzymes as targets in oncology, but also to achieve a better understanding of their biology. In the present study, we investigate the activity of ritanserin, a compound structurally similar to R59022, against DGKα. Ritanserin, originally characterized as a serotonin (5-HT) receptor (5-HTR) antagonist, underwent clinical trials as a potential medicine for the treatment of schizophrenia and substance dependence. We document herein that ritanserin attenuates DGKα kinase activity while increasing the enzyme’s affinity for ATP in vitro. In addition, R59022 and ritanserin function as DGKα inhibitors in cultured cells and activate protein kinase C (PKC). While recognizing that ritanserin attenuates DGK activity, we also find that R59022 and R59949 are 5-HTR antagonists. In conclusion, ritanserin, R59022 and R59949 are combined pharmacological inhibitors of DGKα and 5-HTRs in vitro.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Boroda

Niccum

Raje

et al. 2017

Biochemical Pharmacology

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“…A,B). 18:1/18:1‐ and 16:0/18:1‐PA are relatively abundant species in mammalian (mouse) brain and COS‐7 cells . We recently demonstrated that DGKδ produced 14:0/16:0‐, 14:0/16:1‐, 16:0/16:0‐, 16:0/16:1‐, 16:0/18:0‐, and 16:0/18:1‐PA in glucose‐stimulated C2C12 cells .…”

Section: Discussionmentioning

confidence: 99%

Characterization of α‐synuclein N‐terminal domain as a novel cellular phosphatidic acid sensor

et al. 2019

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Tracking the localization and dynamics of the intracellular bioactive lipid phosphatidic acid (PA) is important for understanding diverse biological phenomena. Although several PA sensors have been developed, better ones are still needed for comprehensive PA detection in cells. We recently found that a-synuclein (a-Syn) selectively and strongly bound to PA in vitro. Here, we revealed that the N-terminal region of a-Syn (a-Syn-N) specifically bound to PA, with a dissociation constant of 6.6 lM. a-Syn-N colocalized with PAproducing enzymes, diacylglycerol kinase (DGK) b at the plasma membrane (PM), myristoylated DGKf at the Golgi apparatus, phorbol ester-stimulated DGKc at the PM, and phospholipase D2 at the PM and Golgi but not with the phosphatidylinositol-4,5-bisphosphate-producing enzyme in COS-7 cells. However, a-Syn-N failed to colocalize with them in the presence of their inhibitors and/or their inactive mutants. These results indicate that a-Syn-N specifically binds to cellular PA and can be applied as an excellent PA sensor.

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“…As a result, current DGK inhibitors consist of compounds with poor specificity within the DGK superfamily (de Chaffoy de Courcelles et al, 1989; de Chaffoy de Courcelles et al, 1985) or lack selectivity measurements against other lipid and protein kinases (Boroda et al, 2017; Liu et al, 2016; Purow, 2015). Thus, methods that provide information on small molecule binding mode and selectivity are needed to guide development of isoform-selective DGK inhibitors.…”

Section: Introductionmentioning

confidence: 99%

The Ligand Binding Landscape of Diacylglycerol Kinases

Franks

Campbell

Purow

et al. 2017

Cell Chemical Biology

109

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SUMMARY Diacylglycerol kinases (DGKs) are integral components of signal transduction cascades that regulate cell biology through ATP-dependent phosphorylation of the lipid messenger diacylglycerol. Methods for direct evaluation of DGK activity in native biological systems are lacking and needed to study isoform-specific functions of these multidomain lipid kinases. Here, we utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to define, for the first time, ATP- and small molecule-binding motifs of representative members from all five DGK subtypes. We use chemical proteomics to discover an unusual binding mode for the DGK-alpha (DGKα) inhibitor ritanserin, including interactions at the atypical C1 domain distinct from the ATP binding region. Unexpectedly, deconstruction of ritanserin yielded a fragment compound that blocks DGKα activity through a conserved binding mode and enhanced selectivity against the kinome. Collectively, our studies illustrate the power of chemical proteomics to profile protein-small molecule interactions of lipid kinases for fragment-based lead discovery.

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

Cited by 63 publications

References 67 publications

Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Dual activities of ritanserin and R59022 as DGKα inhibitors and serotonin receptor antagonists

Characterization of α‐synuclein N‐terminal domain as a novel cellular phosphatidic acid sensor

The Ligand Binding Landscape of Diacylglycerol Kinases

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