Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs

W. Guo, R. Liu, Y. Ono, A.-H. Ma, A. Martinez, E. Sanchez, Y. Wang, W. Huang, A. Mazloom, J. Li, J. Ning, E. Maverakis, K.S. Lam, H.-J. Kung

Research output: Contribution to journalArticle

16 Citations (Scopus)

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. Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics.
Original languageEnglish
Pages (from-to)938-947
Number of pages10
JournalMolecular Pharmacology
Volume82
Issue number5
DOIs
Publication statusPublished - 2012
Externally publishedYes

Fingerprint

Interleukin-2
T-Lymphocytes
Protein-Tyrosine Kinases
Apoptosis
T-Cell Leukemia
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Cutaneous T-Cell Lymphoma
Jurkat Cells
7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo(4,5-g)quinoxalin-6(5H)-one
emt protein-tyrosine kinase
T-Cell Lymphoma
Extracellular Signal-Regulated MAP Kinases
Structure-Activity Relationship
MicroRNAs
Heterografts
Interferons
Autoimmune Diseases
Libraries
Neoplasms
Carcinogenesis

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

Cite this

Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs. / Guo, W.; Liu, R.; Ono, Y.; Ma, A.-H.; Martinez, A.; Sanchez, E.; Wang, Y.; Huang, W.; Mazloom, A.; Li, J.; Ning, J.; Maverakis, E.; Lam, K.S.; Kung, H.-J.

In: Molecular Pharmacology, Vol. 82, No. 5, 2012, p. 938-947.

Research output: Contribution to journalArticle

Guo, W, Liu, R, Ono, Y, Ma, A-H, Martinez, A, Sanchez, E, Wang, Y, Huang, W, Mazloom, A, Li, J, Ning, J, Maverakis, E, Lam, KS & Kung, H-J 2012, 'Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs', Molecular Pharmacology, vol. 82, no. 5, pp. 938-947. https://doi.org/10.1124/mol.112.079889
Guo, W. ; Liu, R. ; Ono, Y. ; Ma, A.-H. ; Martinez, A. ; Sanchez, E. ; Wang, Y. ; Huang, W. ; Mazloom, A. ; Li, J. ; Ning, J. ; Maverakis, E. ; Lam, K.S. ; Kung, H.-J. / Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs. In: Molecular Pharmacology. 2012 ; Vol. 82, No. 5. pp. 938-947.
@article{ecb58e1afe1e4c3d94b9ac9308dde70a,
title = "Molecular characteristics of CTA056, a novel interleukin-2-inducible T-cell kinase inhibitor that selectively targets malignant T cells and modulates oncomirs",
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. Copyright {\circledC} 2012 The American Society for Pharmacology and Experimental Therapeutics.",
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",
author = "W. Guo and R. Liu and Y. Ono and A.-H. Ma and A. Martinez and E. Sanchez and Y. Wang and W. Huang and A. Mazloom and J. Li and J. Ning and E. Maverakis and K.S. Lam and H.-J. Kung",
note = "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: hkung@ucdavis.edu 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; Bunnell, S.C., Henry, P.A., Kolluri, R., Kirchhausen, T., Rickles, R.J., Berg, L.J., Identification of Itk/Tsk Src homology 3 domain ligands (1996) Journal of Biological Chemistry, 271 (41), pp. 25646-25656. , DOI 10.1074/jbc.271.41.25646; Chen, Y.Q., Wang, X.X., Yao, X.M., Zhang, D.L., Yang, X.F., Tian, S.F., Wang, N.S., MicroRNA-195 promotes apoptosis in mouse podocytes via enhanced caspase activity driven by BCL2 insufficiency (2011) Am J Nephrol, 34, pp. 549-559; Cook, B.N., Bentzien, J., White, A., Nemoto, P.A., Wang, J., Man, C.C., Soleymanzadeh, F., Takahashi, H., Discovery of potent inhibitors of interleukin-2 inducible T-cell kinase (ITK) through structure-based drug design (2009) Bioorg Med Chem Lett, 19, pp. 773-777; Dancey, G., Violet, J., Malaroda, A., Green, A.J., Sharma, S.K., Francis, R., Othman, S., Griffin, N., A phase i clinical trial of CHT-25 a 131I-labeled chimeric anti-CD25 antibody showing efficacy in patients with refractory lymphoma (2009) Clin Cancer Res, 15, pp. 7701-7710; 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year = "2012",
doi = "10.1124/mol.112.079889",
language = "English",
volume = "82",
pages = "938--947",
journal = "Molecular Pharmacology",
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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: hkung@ucdavis.edu 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

VL - 82

SP - 938

EP - 947

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 5

ER -