2. Academic Validation
  3. Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia

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

  • Leukemia. 2016 Jan;30(1):173-81. doi: 10.1038/leu.2015.180.
H Wu 1 2,  C Hu 1,  A Wang 1 2,  E L Weisberg 3,  Y Chen 1,  C-H Yun 4,  W Wang 1,  Y Liu 3,  X Liu 1 2,  B Tian 5,  J Wang 4,  Z Zhao 1,  Y Liang 4,  B Li 1,  L Wang 1,  B Wang 1,  C Chen 1,  S J Buhrlage 4,  Z Qi 1,  F Zou 1,  A Nonami 3,  Y Li 3,  S M Fernandes 3,  S Adamia 3,  R M Stone 3,  I A Galinsky 3,  X Wang 6,  G Yang 3,  J D Griffin 3,  J R Brown 3,  M J Eck 4,  J Liu 1,  N S Gray 4,  Q Liu 1 2 7
Affiliations

Affiliations

  • 1 High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
  • 2 University of Science and Technology of China, Anhui, Hefei, P. R. China.
  • 3 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 5 Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing, China.
  • 6 Department of Lymphoma, Sino-US Center for Lymphoma and Leukemia, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
  • 7 Hefei Science Center, Chinese Academy of Sciences, Hefei, Anhui, China.
PMID: 26165234 DOI: 10.1038/leu.2015.180
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.

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