Tomivosertib

Tomivosertib (CAS No. 1849590-01-7) is a potent, highly selective, orally active MNK1 and MNK2 inhibitor. By directly inhibiting MNK1/2, it blocks phosphorylation activation of eukaryotic translation initiation factor 4E (eIF4E) at Ser209, and is involved in regulating the MNK-eIF4E signaling pathway, the AMPK-MNK-eIF4E metabolic pathway, and upstream RAS/RAF/MEK/ERK and p38 MAPK signaling pathways. The IC50 is 2.4 nM for MNK1 and 1 nM for MNK2.

Commonly used concentrations in cell culture are 25 nM (human dorsal root ganglion neurons), 0.1–10 μM (acute myeloid leukemia cells), 10–40 μM (glioblastoma cells and related endothelial cells), and 1 μM (mouse hepatocytes), mainly for evaluating eIF4E phosphorylation, cell proliferation / apoptosis, angiogenesis, spontaneous neuronal firing, and metabolism-related indicators.

Common dosing in animal studies is 10 mg/kg (pancreatic cancer mice, oral gavage) and 2 mg/kg (glioblastoma mice, oral), used to inhibit tumor growth, angiogenesis, and regulate ketogenesis.

References:

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[2] Suarez M, Blyth GT, Mina AA, Kosciuczuk EM, Dolniak B, Dinner S, Altman JK, Eklund EA, Saleiro D, Beauchamp EM, Platanias LC. Inhibitory effects of Tomivosertib in acute myeloid leukemia. Oncotarget. 2021 May 11;12(10):955-966. doi: 10.18632/oncotarget.27952. PMID: 34012509; PMCID: PMC8121614.

[3] Zhang Q, Zhao J, Xu T. Inhibition of eukaryotic initiation factor 4E by tomivosertib suppresses angiogenesis, growth, and survival of glioblastoma and enhances chemotherapy's efficacy. Fundam Clin Pharmacol. 2023 Aug;37(4):807-815. doi: 10.1111/fcp.12877. Epub 2023 Feb 7. PMID: 36691859.

[4] Yang H, Zingaro VA, Lincoff J, Tom H, Oikawa S, Oses-Prieto JA, Edmondson Q, Seiple I, Shah H, Kajimura S, Burlingame AL, Grabe M, Ruggero D. Remodelling of the translatome controls diet and its impact on tumorigenesis. Nature. 2024 Sep;633(8028):189-197. doi: 10.1038/s41586-024-07781-7. Epub 2024 Aug 14. PMID: 39143206; PMCID: PMC12147720.

[5] Li Y, Uhelski ML, North RY, Mwirigi JM, Tatsui CE, McDonough KE, Cata JP, Corrales G, Dussor G, Price TJ, Dougherty PM. Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy. Brain. 2024 Sep 3;147(9):2991-2997. doi: 10.1093/brain/awae178. PMID: 39046204; PMCID: PMC11370786.