Mitogen-activated protein kinase-interacting kinases 1 and 2 (MNK1 and MNK2) phosphorylate the oncogene eIF4E on serine 209. This phosphorylation has been reported to be required for its oncogenic activity. Eukaryotic initiation factor 4E (eIF4E) is a key component of the translational machinery and an important modulator of cell growth and proliferation. The activity of eIF4E is thought to be regulated by interaction with inhibitory binding proteins (4E-BPs) and phosphorylation by mitogen-activated protein (MAP) kinase-interacting kinase (MNK) on Ser209 in response to mitogens and cellular stress.
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eFT508 (Tomivosertib) is a potent, highly selective, reversible, ATP-competitive, and orally bioavailable MNK1 and MNK2 inhibitor with IC50 of 1-2 nM in enzyme assays; dose-dependently reduces eIF4E phosphorylation at Serine 209 in tumor cell lines with IC50 of 2-16 nM; shows anti-proliferative activity against multiple DLBCL cell lines, decreases the production of pro-inflammatory cytokines including TNFα, IL-6, IL-10 and CXCL10; demonstrates significant anti-tumor activity in human lymphoma xenograft models which harbor activating MyD88 mutations.
A broad-spectrum natural antifungal compound that acts as a selective and highly potent fungal Pkc1 kinase inhibitor; potent,y and ATP-competitively inhibits C. albicans Pkc (CaPkc1) kinase with IC50 of <40 nM, Ki of 7 nM; shows potent antifungal activity with MIC of 10 ug/ml against both C. albicans and A. fumigatus; also is a potent, selective, orally bioavailable Mnk inhibitor with IC50 of 116 nM and 11 nM for Mnk1 and Mnk2, respectively; blocks eIF4E phosphorylation in cancer cells, inducing apoptosis, suppressing proliferation, and reducing soft agar colonization; active in tumor xenograft model.
A cell-permeable, specific MNK1 inhibitor with IC50 of 2.2 uM; has no inhibitory activity on p38, JNK1, ERK1/2, etc.; inhibits phosphorylation of eIF4E in cellular assays with IC50 of 3 uM.
MNKI-19(MNKI19 is a potent and dual-specific Mnk inhibitor with Ki of 186 nM and 68 nM for Mnk1 and Mnk2, respectively; only displays moderate activity against Pim-1 (Ki=2.35 uM) in a panel of upstream activating kinases of Mnks, including B-Raf, MAPK1, MAPK2, Akt1, PI3K, p38α, and mTOR; inhibits the phosphorylation of eIF4E and 4E-BP1, arrests cancer cells in the G1 phase and induce apoptosis in FLT3-ITD expressed AML cells.
ETC-206 (ETC-1907206) is a novel potent, selective MNK1/2 inhibitor with IC50 of 64/86 nM, inhibits eIF4E phosphorylation inhibition in HeLa cell line with IC50 of 321 nM; displays excellent kinase selectivity, inhibits only 2 kinases by >65% at 1 uM against a panel of 104 kinases; demonstrates potent anti-proliferative activity against 25 hematological cancer cell lines with submicromolar IC50, especially against GK-5, DOHH2, AHH1 and P3HR-1 cell lines; prevents BC CML LSC self-renewal in vitro, significantly enhances the anti-tumor activity of dasatinib in BC CML mouse xenograft model.
QL-X-138 is a selective and potent BTK/MNK dual kinase inhibitor with IC50 of 8, 107.4, and 26 nM for BTK, MNK1, and MNK2, respectively; exhibits covalent binding to BTK and noncovalent binding to MNK; enhances the antiproliferative efficacies in vitro against a variety of B-cell cancer cell lines, as well as AML and CLL primary patient cells; arrests cell cycle progression and strongly induces apoptosis.
MNK inhibitor 54
MNK inhibitor 54 is a potent, orally bioavailable dual MNK1/2 and BCR-ABL1 inhibitor with IC50 of 20/10/200/10 nM for Abl T315I/ wt Abl/MNK1/MNK2, respectively; also inhibits RET, FLT3, VEGFR2 with IC50 <20 nM; shows GI50 of 51 nM in the growth of K562 cells overexpressing eIF4E; exhibits antitumor activity in a mouse xenograft model and also reduces the level of phosphorylated eukaryotic translation initiation factor 4E in the tumor tissues.
MNKI-85 is a potent and selective Mnk2 inhibitor with Ki of 31 nM, displays no inhibitory activities against Mnk1, CDK2A, CDK9T, and CDK4D; effectively inhibits the growth of AML cells that possess an M5 subtype with FLT3-internal tandem duplication mutation, a powerful pharmacologic tool in studying the Mnk2/eIF4E-mediated tumorigenic mechanism.
MNK inhibitor 9
MNK inhibitor 9 is a potent, selective MAPK-interacting kinase (MNK1 and MNK2) inhibitor with IC50 of 3 nM for both, with no activity aginst CDK1/2 (IC50>25 uM); displays excellent selectivity against a 53 kinase panel, with 4 kinases with IC50 <1 uM; inhibits eIF4E phosphorylation in KMS11-luc myeloma with IC50 of 0.6 nM, exhibits inhibition of cell proliferation in human multiple myeloma tumor cell line with EC50 of 1.7 uM; has good solubility and permeability, and is a suitable in vivo tool compound.
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