Document Detail


Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs.
MedLine Citation:
PMID:  22899868     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-16
Journal Detail:
Title:  Molecular pharmacology     Volume:  82     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-22     Completed Date:  2013-02-12     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  938-47     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Medicine,,University of California Davis, Sacramento, California 95817, USA.
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MeSH Terms
Descriptor/Qualifier:
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:
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:
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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