Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia

H. Wu, C. Hu, A. Wang, E. L. Weisberg, Y. Chen, C. H. Yun, W. Wang, Y. Liu, X. Liu, B. Tian, J. Wang, Z. Zhao, Y. Liang, B. Li, L. Wang, B. Wang, C. Chen, S. J. Buhrlage, Z. Qi, F. ZouA. Nonami, Y. Li, S. M. Fernandes, S. Adamia, R. M. Stone, I. A. Galinsky, X. Wang, G. Yang, J. D. Griffin, J. R. Brown, M. J. Eck, J. Liu, N. S. Gray, Q. Liu

Research output: Contribution to journalArticle

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Abstract

Bruton's tyrosine kinase (BTK) kinase is a member of the TEC kinase family and is a key regulator of the B-cell receptor (BCR)-mediated signaling pathway. It is important for B-cell maturation, proliferation, survival and metastasis. Pharmacological inhibition of BTK is clinically effective against a variety of B-cell malignances, such as mantle cell lymphoma, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and activated B-cell-diffuse large B-cell lymphoma. MNK kinase is one of the key downstream regulators in the RAF-MEK-ERK signaling pathway and controls protein synthesis via regulating the activity of eIF4E. Inhibition of MNK activity has been observed to moderately inhibit the proliferation of AML cells. Through a structure-based drug-design approach, we have discovered a selective and potent BTK/MNK dual kinase inhibitor (QL-X-138), which exhibits covalent binding to BTK and noncovalent binding to MNK. Compared with the BTK kinase inhibitor (PCI-32765) and the MNK kinase inhibitor (cercosporamide), QL-X-138 enhanced the antiproliferative efficacies in vitro against a variety of B-cell cancer cell lines, as well as AML and CLL primary patient cells, which respond moderately to BTK inhibitor in vitro. The agent can effectively arrest the growth of lymphoma and leukemia cells at the G0-G1 stage and can induce strong apoptotic cell death. These primary results demonstrate that simultaneous inhibition of BTK and MNK kinase activity might be a new therapeutic strategy for B-cell malignances.

Original languageEnglish
Pages (from-to)173-181
Number of pages9
JournalLeukemia
Volume30
Issue number1
DOIs
Publication statusPublished - Jan 1 2016
Externally publishedYes

Fingerprint

Lymphoma
Leukemia
Phosphotransferases
B-Lymphocytes
Acute Myeloid Leukemia
B-Cell Chronic Lymphocytic Leukemia
Mantle-Cell Lymphoma
Lymphoma, Large B-Cell, Diffuse
MAP Kinase Signaling System
Drug Design
Myeloid Cells
Agammaglobulinaemia tyrosine kinase
Cell Death
Cell Proliferation
Pharmacology
Neoplasm Metastasis
Cell Line
Survival
Growth
Neoplasms

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Wu, H., Hu, C., Wang, A., Weisberg, E. L., Chen, Y., Yun, C. H., ... Liu, Q. (2016). Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia, 30(1), 173-181. https://doi.org/10.1038/leu.2015.180

Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. / Wu, H.; Hu, C.; Wang, A.; Weisberg, E. L.; Chen, Y.; Yun, C. H.; Wang, W.; Liu, Y.; Liu, X.; Tian, B.; Wang, J.; Zhao, Z.; Liang, Y.; Li, B.; Wang, L.; Wang, B.; Chen, C.; Buhrlage, S. J.; Qi, Z.; Zou, F.; Nonami, A.; Li, Y.; Fernandes, S. M.; Adamia, S.; Stone, R. M.; Galinsky, I. A.; Wang, X.; Yang, G.; Griffin, J. D.; Brown, J. R.; Eck, M. J.; Liu, J.; Gray, N. S.; Liu, Q.

In: Leukemia, Vol. 30, No. 1, 01.01.2016, p. 173-181.

Research output: Contribution to journalArticle

Wu, H, Hu, C, Wang, A, Weisberg, EL, Chen, Y, Yun, CH, Wang, W, Liu, Y, Liu, X, Tian, B, Wang, J, Zhao, Z, Liang, Y, Li, B, Wang, L, Wang, B, Chen, C, Buhrlage, SJ, Qi, Z, Zou, F, Nonami, A, Li, Y, Fernandes, SM, Adamia, S, Stone, RM, Galinsky, IA, Wang, X, Yang, G, Griffin, JD, Brown, JR, Eck, MJ, Liu, J, Gray, NS & Liu, Q 2016, 'Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia', Leukemia, vol. 30, no. 1, pp. 173-181. https://doi.org/10.1038/leu.2015.180
Wu H, Hu C, Wang A, Weisberg EL, Chen Y, Yun CH et al. Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia. 2016 Jan 1;30(1):173-181. https://doi.org/10.1038/leu.2015.180
Wu, H. ; Hu, C. ; Wang, A. ; Weisberg, E. L. ; Chen, Y. ; Yun, C. H. ; Wang, W. ; Liu, Y. ; Liu, X. ; Tian, B. ; Wang, J. ; Zhao, Z. ; Liang, Y. ; Li, B. ; Wang, L. ; Wang, B. ; Chen, C. ; Buhrlage, S. J. ; Qi, Z. ; Zou, F. ; Nonami, A. ; Li, Y. ; Fernandes, S. M. ; Adamia, S. ; Stone, R. M. ; Galinsky, I. A. ; Wang, X. ; Yang, G. ; Griffin, J. D. ; Brown, J. R. ; Eck, M. J. ; Liu, J. ; Gray, N. S. ; Liu, Q. / Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. In: Leukemia. 2016 ; Vol. 30, No. 1. pp. 173-181.
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