Zotatifin

Zotatifin (eFT226) is a potent, selective, and well-tolerated eIF4A inhibitor. Zotatifin promotes eIF4A binding to specific mRNA sequences with recognition motifs in the 5’-UTRs (IC₅₀=2 nM) and interferes with the assembly of the eIF4F initiation complex^[1]. Zotatifin shows robust antiviral effects, it effectively reduces viral infectivity by inhibiting SARS-CoV-2 NP protein biogenesis (IC₉₀=37 nM)^[2]. Zotatifin induces cell apoptosis^[1]. IC50 & Target: IC50: 2 nM (eIF4A)^[1]
IC90: 37 nM (NP-staining assay)^[2] In Vitro: Zotatifin induces the formation of a stable ternary complex [eIF4A-RNA-eFT226]. Zotatifin increases the residence time for eIF4A1 binds to an AGAGAG RNA surface, the K_d values are 0.021 μM and 8.0 μM, respectively for eFT226 presence or absence^[1].
Zotatifin inhibits in vitro translation as a sequence-dependent manner, the IC₅₀ values are 1.5 nM, 13.8 nM, 92.5 nM, and 217.5 nM, respectively in an MDA-MB-231 cell line with transiently transfected AGAGAG, GGCGGC, CCGCCG and CAACAA 5’-UTRs-containing sequences^[1].
Zotatifin (0.0001 μM-1 μM; 72 hours) inhibits tumor cells growth as a dose-dependent manner. It shows a potent anti-proliferative activity (GI₅₀<15 nM) in MDA-MB-231 tumor cells, but eIF4A1 F163L mutation rescues eFT226 anti-proliferative activity^[1].
Zotatifin (0.0001 μM-1 μM; 72 hours) inhibits tumor cell growth, exhibits GI₅₀ values for TMD8, SU-DHL-2, HBL1, Pfeiffer, SU-DHL-6, SU-DHL-10, VAL, Carnaval, U2973, Ramos, Jeko1, Mino, and Rec-1 cells are 4.1 nM, 3 nM, 5.6 nM, 3.7 nM, 5.3 nM, 7.3 nM, 6.6 nM, 4.4 nM, 4.2 nM, 4.6 nM, 7.9 nM, 11.2 nM and 11.8 nM, respectively^[1].
Zotatifin (30 μM-100 μM; 3 or 24 hours) results in translational regulation of oncogenic protein, decreases MYC,CCND3,BCL2 and MCL1 protein expression as a time- and dose-dependent manner^[1].
The anti-viral activity of Zotatifin is demonstrated by various assays: such as TCID50 assay, Plaque assay, NP-staining assay, et al^[2].
Zotatifin (10 nM, 100 nM, 200 nM, 500 nM, 2 μM, 10 μM; 1 or 2 hours pre-treatment before virus isolates) decreases the detection of the viral NP protein and reduces viral infectivity in a concentration-dependent matter in Vero E6 cells cells infected with SARS-CoV-2 isolates^[2].
In Vivo: Zotatifin (intravenous injection; 1 mg/kg; 14-22 days) decreases tumor volume, inhibits the TMD8 xenograft-bearing, HBL1 xenograft-bearing, Pfeiffer xenograft-bearing, SU-DHL-6 xenograft-bearing, SU-DHL-10 xenograft-bearing and Ramos-bearing animals’tumor growth as percentage of 97%, 87%, 70%, 83%, 37% and 75%, respectively^[1].
Zotatifin (intravenous injection; 0.001 mg/kg-1 mg/kg; 15 days) inhibits the growth of B-cell lymphoma xenografts and is well-tolerated against B-cell lymphoma xenograft models in vivo^[1].