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Molecular Pharmacology

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Research ArticleArticle

Molecular Characteristics of CTA056, a Novel Interleukin-2-Inducible T-Cell Kinase Inhibitor that Selectively Targets Malignant T Cells and Modulates Oncomirs

Wenchang Guo, Ruiwu Liu, Yoko Ono, Ai-Hong Ma, Anthony Martinez, Eduardo Sanchez, Yan Wang, Wenzhe Huang, Anisha Mazloom, Jixian Li, Jinying Ning, Emanual Maverakis, Kit S. Lam and Hsing-Jien Kung
Molecular Pharmacology November 2012, 82 (5) 938-947; DOI: https://doi.org/10.1124/mol.112.079889
Wenchang Guo
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Ruiwu Liu
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Yoko Ono
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Ai-Hong Ma
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Anthony Martinez
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Eduardo Sanchez
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Yan Wang
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Wenzhe Huang
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Anisha Mazloom
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Jixian Li
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Jinying Ning
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Emanual Maverakis
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Kit S. Lam
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Hsing-Jien Kung
Departments of Biochemistry and Molecular Medicine (W.G., R.L., A.-H.M., A.M., E.S., Y.W., W.H., A.M., K.S.L., H.-J.K.) and Dermatology (Y.O., E.M.), University of California Davis, Sacramento, California; and Crown Bioscience, Inc., Beijing, China (J.L., J.N.)
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Abstract

Interleukin-2-inducible T-cell kinase (Itk) is a member of the Btk (Bruton's tyrosine kinase) family of tyrosine kinases. Itk plays an important role in normal T-cell functions and in the pathophysiology of both autoimmune diseases and T-cell malignancies. Here, we describe the initial characterization of a selective inhibitor, 7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one (CTA056), that was developed through screening a 9600-compound combinatorial solution phase library, followed by molecular modeling, and extensive structure-activity relationship studies. CTA056 exhibits the highest inhibitory effects toward Itk, followed by Btk and endothelial and epithelial tyrosine kinase. Among the 41 cancer cell lines analyzed, CTA056 selectively targets acute lymphoblastic T-cell leukemia and cutaneous T-cell lymphoma. Normal T cells are minimally affected. Incubation of Jurkat and MOLT-4 cells with CTA056 resulted in the inhibition of the phosphorylation of Itk and its effectors including PLC-γ, Akt, and extracellular signal-regulated kinase, as well as the decreased secretion of targeted genes such as interleukin-2 and interferon-γ. Jurkat cells also underwent apoptosis in a dose-dependent manner when incubated with CTA056. The potent apoptosis-inducing potential of CTA056 is reflected by the significant modulation of microRNAs involved in survival pathways and oncogenesis. The in vitro cytotoxic effect on malignant T cells is further validated in a xenograft model. The selective expression and activation of Itk in malignant T cells, as well as the specificity of CTA056 for Itk, make this molecule a potential therapeutic agent for the treatment of T-cell leukemia and lymphoma.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK52659]; the National Institutes of Health National Cancer Institute [Grants CA150197, CA098116]; C-Tag Bioscience, Inc.; a U.S. Department of Defense postdoctoral training award [Grant PC080859] and Auburn Community Cancer Endowment Fund (to W.G.); and an early career award from the Howard Hughes Medical Institute, the Burroughs Wellcome Fund, and the Martin and Dorothy Spatz Charitable Foundation (to E.M.).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.079889.

  • ABBREVIATIONS:

    T-ALL
    T-cell acute lymphoblastic leukemia
    Itk
    interleukin-2-inducible T-cell kinase
    Btk
    Bruton's tyrosine kinase
    Etk
    endothelial and epithelial tyrosine kinase
    miRNA
    microRNA
    PI
    propidium iodide
    DIEA
    N,N-diisopropylethylamine
    DMF
    N,N-dimethylformamide
    Pd/C
    palladium on carbon
    DMSO
    dimethyl sulfoxide
    RP-HPLC
    reversed-phase high-performance liquid chromatography
    TLC
    thin-layer chromatography
    DTT
    dithiothreitol
    CTA056
    7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    IL
    interleukin
    IFN
    interferon
    PCR
    polymerase chain reaction
    ELISA
    enzyme-linked immunosorbent assay
    ANOVA
    analysis of variance.

  • Received May 8, 2012.
  • Accepted August 16, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (5)
Molecular Pharmacology
Vol. 82, Issue 5
1 Nov 2012
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Research ArticleArticle

Itk Inhibitors and T-Cell Leukemia/Lymphomas

Wenchang Guo, Ruiwu Liu, Yoko Ono, Ai-Hong Ma, Anthony Martinez, Eduardo Sanchez, Yan Wang, Wenzhe Huang, Anisha Mazloom, Jixian Li, Jinying Ning, Emanual Maverakis, Kit S. Lam and Hsing-Jien Kung
Molecular Pharmacology November 1, 2012, 82 (5) 938-947; DOI: https://doi.org/10.1124/mol.112.079889

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Research ArticleArticle

Itk Inhibitors and T-Cell Leukemia/Lymphomas

Wenchang Guo, Ruiwu Liu, Yoko Ono, Ai-Hong Ma, Anthony Martinez, Eduardo Sanchez, Yan Wang, Wenzhe Huang, Anisha Mazloom, Jixian Li, Jinying Ning, Emanual Maverakis, Kit S. Lam and Hsing-Jien Kung
Molecular Pharmacology November 1, 2012, 82 (5) 938-947; DOI: https://doi.org/10.1124/mol.112.079889
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