title: Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia.
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.
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.|University of Science and Technology of China, Anhui, Hefei, P. R. China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: C
authors.initials: C
authors.lastname: Hu
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.|University of Science and Technology of China, Anhui, Hefei, P. R. China.
authors.forename: A
authors.initials: A
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Weisberg
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Yun
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.|University of Science and Technology of China, Anhui, Hefei, P. R. China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology and Visual Science Key Laboratory, Beijing, China.
authors.forename: B
authors.initials: B
authors.lastname: Tian
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Buhrlage
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Qi
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: F
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nonami
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Fernandes
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Adamia
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Galinsky
authors.affiliation: 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.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Griffin
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: M J
authors.initials: MJ
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authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors.forename: N S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, China.|University of Science and Technology of China, Anhui, Hefei, P. R. China.|Hefei Science Center, Chinese Academy of Sciences, Hefei, Anhui, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C491395:MKNK1 protein, human; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C486342:MKNK2 protein, human; D017346:Protein Serine-Threonine Kinases