| Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs. | |
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MedLine Citation:
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PMID: 22899868 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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; Hsing-Jien Kung |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-08-16 |
Journal Detail:
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Title: Molecular pharmacology Volume: 82 ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-10-22 Completed Date: 2013-02-12 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 938-47 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Medicine,,University of California Davis, Sacramento, California 95817, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / chemistry*, pharmacology Apoptosis / drug effects Benzimidazoles / chemical synthesis, chemistry*, pharmacology Cell Line, Tumor Drug Screening Assays, Antitumor Humans Interferon-gamma / antagonists & inhibitors, secretion Interleukin-2 / antagonists & inhibitors*, secretion Lymphoma, T-Cell, Cutaneous Mice Mice, Nude MicroRNAs / metabolism* Models, Molecular Neoplasm Transplantation Phosphorylation Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Protein-Tyrosine Kinases / antagonists & inhibitors*, metabolism Quinazolines / chemical synthesis, chemistry*, pharmacology T-Lymphocytes / drug effects*, enzymology, pathology Transplantation, Heterologous Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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CA098116/CA/NCI NIH HHS; CA150197/CA/NCI NIH HHS; DK52659/DK/NIDDK NIH HHS; PC080859/PC/NCI NIH HHS; //Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo(4,5-g)quinoxalin-6(5H)-one; 0/Antineoplastic Agents; 0/Benzimidazoles; 0/Interleukin-2; 0/MicroRNAs; 0/Quinazolines; 82115-62-6/Interferon-gamma; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.2/emt protein-tyrosine kinase |
| Comments/Corrections | |
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