Tomivosertib is an orally active MNK1/2 inhibitor (IC50 = 1–2nM). Tomivosertib specifically downregulates the translation of key oncogenic factors (Cyclin D1 and c-Myc) and immune checkpoint proteins (PD-L1) by inhibiting the phosphorylation of eIF4E at serine 209. Tomivosertib can be used in research related to acute myeloid leukemia, breast cancer, lymphoma, non‑small cell lung cancer, and prostate cancer[1-4].
In vitro, Tomivosertib (0–100nM) treated breast cancer cell lines (MDA‑MB‑231, MDA‑MB‑468, MCF7, T47D, SUM149) for 24 hours. Tomivosertib significantly inhibited the expression of PD‑L1 and PD‑L2, suppressed eIF4E phosphorylation, inhibited global translation, and increased chemosensitivity[5]. Tomivosertib (0.1–10μM) treated acute myeloid leukemia cell lines such as U937, MV411, and MM6 for 1–4 hours. Tomivosertib significantly inhibited phosphorylation of eIF4E at serine 209, reduced cell viability, and impaired clonogenic capacity[6].
In vivo, Tomivosertib (10mg/kg; five days per week) was administered orally to pancreatic cancer mouse models, combined with a ketogenic diet, for two weeks. Tomivosertib significantly suppressed pancreatic tumor growth, lowered blood β‑hydroxybutyrate levels, and inhibited the translation of PPARα and Hmgcs2 in the liver[7]. Tomivosertib (10mg/kg; daily oral administration) was given to C57BL/6J wild‑type (WT) mice, 4EKI mice, or MNK1 knockout (KO) mice that had undergone spared nerve injury (SNI) surgery, for 7 days. Tomivosertib reversed the deficits in rule-shifting tasks, spontaneous pain in SNI mice, and rescued the shortening of the axon initial segment (AIS) in the medial prefrontal cortex (mPFC)[8].
References:
[1] Kevin R. Webster, Vikas K Goel, et al. eFT508, a Potent and Selective Mitogen-Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 Inhibitor, Is Efficacious in Preclinical Models of Diffuse Large B-Cell Lymphoma (DLBCL). Blood 2015; 126 (23): 1554.
[2] Xu Y, Poggio M, Jin HY, et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat Med. 2019 Feb;25(2):301-311.
[3] Li Y, Uhelski ML, North RY, et al. Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy. Brain. 2024 Sep 3;147(9):2991-2997.
[4] Yang X, Liu Z, Yin X, et al. Inhibition MNK-eIF4E-β-catenin preferentially sensitizes gastric cancer to chemotherapy. Fundam Clin Pharmacol. 2022 Aug;36(4):712-720.
[5] Yang ZY, Jiang CW, Zhang WL, et al. Treatment with eFT-508 increases chemosensitivity in breast cancer cells by modulating the tumor microenvironment. J Transl Med. 2022 Jun 18;20(1):276.
[6] Suarez M, Blyth GT, Mina AA, et al. Inhibitory effects of Tomivosertib in acute myeloid leukemia. Oncotarget. 2021 May 11;12(10):955-966.
[7] Yang H, Zingaro VA, Lincoff J, et al. Remodelling of the translatome controls diet and its impact on tumorigenesis. Nature. 2024 Sep;633(8028):189-197.
[8] Shiers S, Mwirigi J, Pradhan G, et al. Reversal of peripheral nerve injury-induced neuropathic pain and cognitive dysfunction via genetic and tomivosertib targeting of MNK. Neuropsychopharmacology. 2020 Feb;45(3):524-533.