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. 2016 Jan;30(1):173-81.
doi: 10.1038/leu.2015.180. Epub 2015 Jul 13.

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

Affiliations

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

H Wu et al. Leukemia. 2016 Jan.

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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Conflict of interest statement

Conflict of Interest

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. Discovery of the BTK/MNK dual kinase inhibitor QL-X-138
(A) Illustration of the rational design concept in X-ray structure of BTK and MNK kinase, BTK(cynate: PDB ID: 3GEN), MNK2(gray, PDB ID:2HW7) (B) Chemical structure of Torin2 and QL-X-138. (C) IP kinase assay of BTK wt and BTKC481S against QL-X-138. (D) IP kinase assay of MNK1/2 wt and MNK1 (C190S), MNK2(C225S) against QL-X-138.
Fig. 2
Fig. 2. Demonstrating of binding mode of QL-X-138 and selectivity profiling
(A) TreeSpot demonstration of QL-X-138 selectivity against a panel of 452 kinases with DiscoveRx KinomeScan technology with a S score =1. (B) Invitrogen biochemical IC50 of BTK, JAK3, MNK1/2 kinases. (C)Anti-proliferation effect of QL-X-138 against TEL-fused JAK3-BaF3 cells. (D)X-ray crystal structure of QL-X-138 with EGFR (T790M) (PDB ID: 4WD5). (E) Molecular modeling of the binding mode of QL-X-138 with BTK kinase (PDB ID: 3GEN). (F) Molecular modeling demonstration of the designed irreversible binding mode of QL-X-138 with MNK2 kinase (PDB ID: 2HW7). (G) Reversible binding mode analysis of QL-X-138 with MNK2 kinase (PDB ID: 2HW7).
Fig. 3
Fig. 3. Effect of QL-X-138 on BTK- and MNK-mediated signaling pathways
(A) Effect of QL-X-138 on signaling in the Ramos cell line. (B) Effect of QL-X-138 on signaling in the OCI-AML3 cell line. (C) Effect of QL-X-138 on signaling in the U2932 cell line (D) Effect of QL-X-138 on signaling in the TMD8 cell line. (E) Effect of QL-X-138 on signaling in the U937 cell line.
Fig. 4
Fig. 4. QL-X-138 arrest of cell cycle progression in a dose dependent manner
(A) Flow cytometry illustration of the effect of QL-X-138 on cell cycle progression arrest in Ramos, OCI-AML-3, U937 and U2932 cells with different concentrations and time points. (B) Quantification of the cell cycle stage distribution (bar graph). (C) Effect of QL-X-138 on cell cycle progression (table).
Fig. 5
Fig. 5. QL-X-138 demonstrates a time and dose-dependent effect on induction of apoptosis
(A) QL-X-138 induction of apoptosis at different times and concentrations in Ramos cells. (B) QL-X-138 induction of apoptosis at different times and concentrations in OCI-AML3 cells. (C) QL-X-138 effect on induction of apoptosis at different concentrations in U937 cells. (D) QL-X-138 induction of apoptosis at different concentrations in U2932 cells.
Fig. 6
Fig. 6
QL-X-138 demonstrates anti-proliferation activity against CLL and AML primary patient cells. All primary cells were cultured and treated for QL-X-138 for 72h before subject to Cell Titer-Glo analysis.

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