Mitogen-activated protein kinase interacting kinases (MNK) 1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. eFT508 Is a potent Inhibitor of MNK1 and MNK2 signaling and tumor growth. In all cell lines tested, eFT508 inhibited Ser209 phosphorylation of eIF4E with IC50 values ranging from 1.4 to 22 nM. This effect of eFT508 on eIF4E Ser209 phosphorylation is specific to MNK1/2 inhibition. Treatment of TMD8 cells for 48 h with eFT508 led to a dose-dependent reduction in secreted IL-6, IL-8, and TNFα. Taken together, eFT508 potently inhibited eIF4E phosphorylation, select mRNA stability, and pro-inflammatory cytokineproduction in DLBCL cells. eFT508 was well-tolerated at doses of 1 and 10 mg/kg QD as measured by lack of body weight loss, which corresponds to aminimal therapeutic index of≥10 in a TMD8 xenograft model. Furthermore, eFT508 treatment produced significant tumor growth inhibition (TGI) over a 10-fold dose range, achieving an average TGI of 71% and 75% when dosed orally at 1 and 10 mg/kg QD, respectively[2].
作用机制
eFT508 makes H-bond interactions with both hinge residues, Lys161 and Met162. The pyridone methyl interacts with the face of Phe159, and the Cys225 sulfur makes a Dunitz interaction[2].
Tomivosertib 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MDA-MB-231
0.31 ± 0.02 nM (IC50)
24 hours
Evaluate the chemosensitivity of MDA-MB-231 cells to Tomivosertib, showing that this cell line is significantly more sensitive to Tomivosertib compared to other cell lines.
J Transl Med. 2022 Jun 18;20(1):276.
MDA-MB-468
1.21 ± 0.01 nM (IC50)
24 hours
Evaluate the chemosensitivity of MDA-MB-468 cells to Tomivosertib, showing that this cell line is significantly more sensitive to Tomivosertib compared to other cell lines.
J Transl Med. 2022 Jun 18;20(1):276.
MCF7
11.38 ± 1.02 nM (IC50)
24 hours
Evaluate the chemosensitivity of MCF7 cells to Tomivosertib, showing that this cell line is significantly more sensitive to Tomivosertib compared to other cell lines.
J Transl Med. 2022 Jun 18;20(1):276.
T47D
10.19 ± 0.01 nM (IC50)
24 hours
Evaluate the chemosensitivity of T47D cells to Tomivosertib, showing that this cell line is significantly more sensitive to Tomivosertib compared to other cell lines.
J Transl Med. 2022 Jun 18;20(1):276.
SUM149
9.14 ± 0.14 nM (IC50)
24 hours
Evaluate the chemosensitivity of SUM149 cells to Tomivosertib, showing that this cell line is significantly more sensitive to Tomivosertib compared to other cell lines.
J Transl Med. 2022 Jun 18;20(1):276.
Mouse dorsal root ganglion (DRG) neurons
25 nM
3 hours
Tomivosertib significantly reduced spontaneous firing induced by IL-6 treatment, indicating its ability to reduce abnormal neuronal activity.
Neuropsychopharmacology. 2020 Feb;45(3):524-533.
CoCaB1, CoCaB14.1, and TM01029 organoids
0.01–10 µM
72 hours
To study the effect of eFT508 on high phospho-eIF4E bladder cancer organoids, results showed that high phospho-eIF4E organoids exhibited a dose-dependent decrease in cell viability in response to eFT508, while low phospho-eIF4E organoids showed no response.
JCI Insight. 2021 Jun 8;6(11):e144920.
Tomivosertib 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Fmr1−/− mouse model
Intraperitoneal injection
1 mg/kg, 3 mg/kg, 5 mg/kg, 8 mg/kg
Once daily for 4 days
Tomivosertib (eFT508) reduces eIF4E phosphorylation by inhibiting MNK activity and ameliorates behavioral and physiological deficits associated with FXS in Fmr1?/? mice.
Neurotherapeutics. 2021 Jan;18(1):624-639
BALB/c mice
Orthotopic xenograft model
IntratumOral injection
1 mg/kg/day
Once daily for 8 weeks
Evaluate the in vivo chemosensitivity of Tomivosertib in breast tumor xenografts, showing that both monotherapy and combination therapy with adriamycin significantly inhibited tumor growth and lung metastasis.
J Transl Med. 2022 Jun 18;20(1):276.
Mice
Peripheral nerve injury (PNI) model
Oral (p.o.) or intraperitoneal (i.p.)
10 mg/kg
Once daily for 7 days
Tomivosertib reversed spontaneous pain and cognitive dysfunction in PNI mice by inhibiting the MNK-eIF4E signaling pathway, and it restored the length of axon initial segments in the prefrontal cortex.
Neuropsychopharmacology. 2020 Feb;45(3):524-533.
Mice
CoCaB1 and TM01029 PDX models
Oral
10 mg/kg
Once daily until the end of the experiment
To study the effect of eFT508 on high phospho-eIF4E PDX models, results showed that high phospho-eIF4E models were sensitive to eFT508, with significantly smaller tumor size and improved survival, while low phospho-eIF4E models showed no response.
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