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Purity: ≥98%
Tomivosertib (also known as eFT508) is a potent, highly selective, reversible, ATP-competitive and orally bioavailable inhibitor of MNK1 and MNK2 (Mitogen-Activated Protein Kinase Interacting Kinase) with IC50 values of 1-2 nM against both isoforms in enzyme assays. Through a reversible, ATP-competitive mechanism of action, eFT508 inhibits the kinase. When eFT508 was applied to tumor cell lines, there was a dose-dependent decrease in the phosphorylation of eIF4E at serine 209 (IC50 = 2-16 nM), which is in line with earlier research showing that MNK1/MNK2 are the only proteins necessary for this site's phosphorylation. eFT508 demonstrated anti-proliferative activity against numerous DLBCL cell lines in a panel of about 50 hematological cancers. TNFα, IL-6, IL-10 and CXCL10 production were all dose-dependently reduced in TMD8, OCI-Ly3, and HBL1 DLBCL cell lines that were sensitive to eFT508 in these cancer cell lines.
| Targets |
MNK1 (IC50 = 1-2 nM); MNK2 (IC50 = 1-2 nM); PD-L1
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| ln Vitro |
Tomivosertib (eFT508) reduces eIF4E phosphorylation at serine 209 in tumor cell lines in a dose-dependent manner (IC50 = 2–16 nM). Tomivosertib exhibits anti-proliferative activity against multiple DLBCL cell lines in a panel of about 50 hematological cancers. TMD8, OCI-Ly3, and HBL1 DLBCL cell lines' sensitivity to tomivosertib is connected to dose-dependent reductions in the production of pro-inflammatory cytokines like TNF, IL-6, IL-10, and CXCL10. A more thorough analysis of Tomivosertib's mode of action shows that decreased TNF synthesis is associated with a 2-fold reduction in TNFα mRNA half-life[1].
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| ln Vivo |
Tomivosertib (eFT508) exhibits significant anti-tumor activity in the TMD8 and HBL-1 ABC-DLBCL models, both of which contain activating MyD88 mutations. Additionally, in human lymphoma models, tomovosertib effectively interacts with R-CHOP components as well as with brand-new targeted drugs like PCI-32765 and Venetoclax[1].
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| Enzyme Assay |
In the pathogenesis of numerous solid tumors and hematological malignancies, messenger RNA (mRNA) translation is dysregulated. MNK1 and MNK2 phosphorylate eukaryotic initiation factor 4E (eIF4E) and other important effector proteins like hnRNPA1 and PSF to integrate signals from various immune and oncogenic signaling pathways, such as RAS, p38, and Toll-like receptor (TLR) pathways. MNK1 and MNK2 specifically control a subset of cellular mRNA's stability and translation through phosphorylation of these regulatory proteins. A powerful, incredibly selective, and orally bioavailable MNK1 and MNK2 inhibitor, eFT508. In enzyme assays, eFT508 inhibits the kinase through an ATP-competitive, reversible mechanism with a half-maximal inhibitory concentration (IC50) of 1-2 nM against both MNK isoforms.
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| Cell Assay |
Treatment of tumor cell lines with eFT508 led to a dose-dependent reduction in eIF4E phosphorylation at serine 209 (IC50 = 2-16 nM), consistent with previous findings that phosphorylation of this site is solely dependent upon MNK1/MNK2. In a panel of ~50 hematological cancers, eFT508 showed anti-proliferative activity against multiple DLBCL cell lines. Sensitivity to eFT508 in TMD8, OCI-Ly3 and HBL1 DLBCL cell lines was associated with dose-dependent decreases in production of pro-inflammatory cytokines including TNFα, IL-6, IL-10 and CXCL10. Further evaluation eFT508 mechanism of action demonstrated that decreased TNFα production correlated with a 2-fold decrease in TNFα mRNA half-life. [1]
Luciferase assay.[2] KRASG12D and MYCTg;KRASG12D cells were transfected in 12-well plates with 200 ng of pGL3 (Firelfy luciferase) constructs containing full-length or mutant 5′UTR of PD-L1 and 40 ng of pRL (Renilla luciferase) plasmid using Lipofectamine 2000 according to the manufacturer’s instructions. Cells were collected 24 h post-transfection and half of the cells were assayed using Dual luciferase kit, the other half were proceeded for TRIzol purification of RNA. Firefly luciferase activity was normalized to Renilla activity, and further normalized to Firefly and Renilla luciferase RNA amounts quantified by RT-qPCR. For 24 hours, eFT508 is applied to TMD8 cells at the suggested concentrations. m7-GTP is used on cell lysates. Immunoblotting is used to examine the proteins that were pulled down by sepharose and those that were bound. |
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| Additional Infomation |
Tomivosertib is under investigation in clinical trial NCT03318562 (A PD Study of Oral eFT508 in Subjects With Advanced TNBC and HCC).
Tomivosertib is an orally bioavailable inhibitor of mitogen-activated protein kinase (MAPK)-interacting serine/threonine-protein kinase 1 (MNK1) and 2 (MNK2), with potential antineoplastic activity. Upon oral administration, tomivosertib binds to and inhibits the activity of MNK1 and 2. This prevents MNK1/2-mediated signaling, and inhibits the phosphorylation of certain regulatory proteins, including eukaryotic translation initiation factor 4E (eIF4E), that regulate the translation of messenger RNAs (mRNAs) involved in tumor cell proliferation, angiogenesis, survival and immune signaling. This inhibits tumor cell proliferation in MNK1/2-overexpressing tumor cells. MNK1/2 are overexpressed in a variety of tumor cell types and promote phosphorylation of eIF4E; eIF4E is overexpressed in many tumor cell types and contributes to tumor development, maintenance and resistance. |
| Molecular Formula |
C17H20N6O2
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| Molecular Weight |
340.38
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| Exact Mass |
340.164
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| Elemental Analysis |
C, 59.99; H, 5.92; N, 24.69; O, 9.40
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| CAS # |
1849590-01-7
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| Related CAS # |
1849590-02-8 (HCl);1849590-01-7;
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| PubChem CID |
118598754
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
735.6±60.0 °C at 760 mmHg
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| Flash Point |
398.7±32.9 °C
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| Vapour Pressure |
0.0±2.4 mmHg at 25°C
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| Index of Refraction |
1.688
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| LogP |
1.12
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
25
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| Complexity |
664
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C2=C(C([H])([H])[H])C([H])=C(C(N2C2(C([H])([H])C([H])([H])C([H])([H])C([H])([H])C2([H])[H])N1[H])=O)N([H])C1C([H])=C(N([H])[H])N=C([H])N=1
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| InChi Key |
HKTBYUWLRDZAJK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H20N6O2/c1-10-7-11(21-13-8-12(18)19-9-20-13)16(25)23-14(10)15(24)22-17(23)5-3-2-4-6-17/h7-9H,2-6H2,1H3,(H,22,24)(H3,18,19,20,21)
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| Chemical Name |
6-[(6-aminopyrimidin-4-yl)amino]-8-methylspiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.44 mg/mL (1.29 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 4.4 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: ≥ 0.43 mg/mL (1.26 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 4.3 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: 0.4 mg/mL (1.18 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 4: 0.4 mg/mL (1.18 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one),suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9379 mL | 14.6895 mL | 29.3789 mL | |
| 5 mM | 0.5876 mL | 2.9379 mL | 5.8758 mL | |
| 10 mM | 0.2938 mL | 1.4689 mL | 2.9379 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05744739 | Recruiting | Procedure: Biospecimen Collection Drug: Tomivosertib |
Acute Myeloid Leukemia | Northwestern University | September 29, 2023 | Phase 1 |
| NCT04622007 | Recruiting | Drug: Tomivosertib Drug: Pemetrexed |
Non-small Cell Lung Cancer | Effector Therapeutics | June 2, 2021 | Phase 2 |
| NCT04261218 | Completed | Drug: tomivosertib Drug: paclitaxel |
Breast Cancer | Translational Research in Oncology |
August 25, 2020 | Phase 2 |
| NCT03616834 | Completed | Drug: Tomivosertib (eFT-508) |
Solid Tumors | Effector Therapeutics | July 25, 2018 | Phase 2 |
| NCT02937675 | Terminated | Drug: Tomivosertib (eFT-508) |
Lymphoma | Effector Therapeutics | February 8, 2017 | Phase 1 Phase 2 |
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