Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 938-947 |
| Number of pages | 10 |
| Journal | Molecular Pharmacology |
| Volume | 82 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2012 |
| Externally published | Yes |
Keywords
- 7 benzyl 1 (3 (piperidin 1 yl)propyl) 2 (4 (pyridin 4 yl)phenyl) 1h imidazo [4,5 g]quinoxalin 6 (5h)one
- antineoplastic agent
- cta 056
- gamma interferon
- interleukin 2
- microRNA
- mitogen activated protein kinase
- protein kinase B
- protein tyrosine kinase
- unclassified drug
- acute lymphoblastic leukemia
- animal cell
- article
- cancer cell culture
- cell specificity
- cell survival
- concentration response
- controlled study
- cutaneous T cell lymphoma
- cytotoxicity
- endothelium cell
- epithelium cell
- gene targeting
- incubation time
- molecular model
- nonhuman
- priority journal
- protein expression
- protein phosphorylation
- structure activity relation
- T cell leukemia
- T lymphocyte
- tumor xenograft
- Animals
- Antineoplastic Agents
- Apoptosis
- Benzimidazoles
- Cell Line, Tumor
- Drug Screening Assays, Antitumor
- Humans
- Interferon-gamma
- Interleukin-2
- Lymphoma, T-Cell, Cutaneous
- Mice
- Mice, Nude
- MicroRNAs
- Models, Molecular
- Neoplasm Transplantation
- Phosphorylation
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Protein-Tyrosine Kinases
- Quinazolines
- T-Lymphocytes
- Transplantation, Heterologous
- Up-Regulation
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In: Molecular Pharmacology, Vol. 82, No. 5, 2012, p. 938-947.
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}
TY - JOUR
T1 - Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs
AU - Guo, W.
AU - Liu, R.
AU - Ono, Y.
AU - Ma, A.-H.
AU - Martinez, A.
AU - Sanchez, E.
AU - Wang, Y.
AU - Huang, W.
AU - Mazloom, A.
AU - Li, J.
AU - Ning, J.
AU - Maverakis, E.
AU - Lam, K.S.
AU - Kung, H.-J.
N1 - 引用次數:13 Export Date: 5 March 2018 CODEN: MOPMA 通訊地址: Kung, H.-J.; University of California Davis, Comprehensive Cancer Center, Department of Biochemistry and Molecular Medicine, 4645 2nd Ave., Sacramento, CA 95817, United States; 電子郵件: [email protected] 化學物質/CAS: gamma interferon, 82115-62-6; interleukin 2, 85898-30-2; mitogen activated protein kinase, 142243-02-5; protein kinase B, 148640-14-6; protein tyrosine kinase, 80449-02-1; 7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo(4,5-g)quinoxalin-6(5H)-one; Antineoplastic Agents; Benzimidazoles; Interferon-gamma, 82115-62-6; Interleukin-2; MicroRNAs; Protein-Tyrosine Kinases, 2.7.10.1; Quinazolines; emt protein-tyrosine kinase, 2.7.10.2 商標: cta 056 參考文獻: Andreotti, A.H., Bunnell, S.C., Feng, S., Berg, L.J., Schreiber, S.L., Regulatory intramolecular association in a tyrosine kinase of the tec family (1997) Nature, 385 (6611), pp. 93-97. , DOI 10.1038/385093a0; Andreotti, A.H., Schwartzberg, P.L., Joseph, R.E., Berg, L.J., T-cell signaling regulated by the Tec family kinase, Itk (2010) Cold Spring Harb Perspect Biol, 2, pp. a002287; August, A., Gibson, S., Kawakami, Y., Kawakami, T., Mills, G.B., Dupont, B., CD28 is associated with and induces the immediate tyrosine phosphorylation and activation of the Tec family kinase ITK/EMT in the human Jurkat leukemic T-cell line (1994) Proceedings of the National Academy of Sciences of the United States of America, 91 (20), pp. 9347-9351; Berg, L.J., Finkelstein, L.D., Lucas, J.A., Schwartzberg, P.L., Tec family kinases in T lymphocyte development and function (2005) Annual Review of Immunology, 23, pp. 549-600. , DOI 10.1146/annurev.immunol.22.012703.104743; Berge, T., Sundvold-Gjerstad, V., Granum, S., Andersen, T.C., Holthe, G.B., Claesson-Welsh, L., Andreotti, A.H., Spurkland, A., T cell specific adapter protein (TSAd) interacts with Tec kinase ITK to promote CXCL12 induced migration of human and murine T cells (2010) PLoS One, 5, pp. e9761; Brown, K., Long, J.M., Vial, S.C., Dedi, N., Dunster, N.J., Renwick, S.B., Tanner, A.J., Cheetham, G.M., Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors (2004) J Biol Chem, 279, pp. 18727-19732; 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PY - 2012
Y1 - 2012
N2 - 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. Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics.
AB - 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. Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics.
KW - 7 benzyl 1 (3 (piperidin 1 yl)propyl) 2 (4 (pyridin 4 yl)phenyl) 1h imidazo [4,5 g]quinoxalin 6 (5h)one
KW - antineoplastic agent
KW - cta 056
KW - gamma interferon
KW - interleukin 2
KW - microRNA
KW - mitogen activated protein kinase
KW - protein kinase B
KW - protein tyrosine kinase
KW - unclassified drug
KW - acute lymphoblastic leukemia
KW - animal cell
KW - article
KW - cancer cell culture
KW - cell specificity
KW - cell survival
KW - concentration response
KW - controlled study
KW - cutaneous T cell lymphoma
KW - cytotoxicity
KW - endothelium cell
KW - epithelium cell
KW - gene targeting
KW - incubation time
KW - molecular model
KW - nonhuman
KW - priority journal
KW - protein expression
KW - protein phosphorylation
KW - structure activity relation
KW - T cell leukemia
KW - T lymphocyte
KW - tumor xenograft
KW - Animals
KW - Antineoplastic Agents
KW - Apoptosis
KW - Benzimidazoles
KW - Cell Line, Tumor
KW - Drug Screening Assays, Antitumor
KW - Humans
KW - Interferon-gamma
KW - Interleukin-2
KW - Lymphoma, T-Cell, Cutaneous
KW - Mice
KW - Mice, Nude
KW - MicroRNAs
KW - Models, Molecular
KW - Neoplasm Transplantation
KW - Phosphorylation
KW - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
KW - Protein-Tyrosine Kinases
KW - Quinazolines
KW - T-Lymphocytes
KW - Transplantation, Heterologous
KW - Up-Regulation
U2 - 10.1124/mol.112.079889
DO - 10.1124/mol.112.079889
M3 - Article
SN - 0026-895X
VL - 82
SP - 938
EP - 947
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 5
ER -