RK-33

RK-33 is an inhibitor of DEAD-box helicase 3 (DDX3), an ATP-dependent RNA helicase.¹ It reduces the helicase activity of Ded1p, the yeast homolog of DDX3, when used at concentrations of 50, 100, and 200 nM. RK-33 reduces the viability of lung cancer cells highly expressing DDX3, including A549, H1299, H23, and H460 cells (IC₅₀s = 4.4-8.4 µM), but not those with low expression of DDX3, such as NCI H3255 cells (IC₅₀ = >25 µM). It sensitizes tumors to stereotactic ablative radiation therapy (SABR) in a Twist1/KRAS^G12D-inducible mouse model of lung cancer when administered at a dose of 20 mg/kg. RK-33 prevents bone metastasis in an MDA-MB-231-Luc breast cancer mouse xenograft model.² It also reduces replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), decreases the levels of SARS-CoV-2 non-structural protein 8 (nsp8) and open reading frame 7a (ORF7a), and inhibits apoptosis in SARS-CoV-2-infected Vero E6 cells when used at a concentration of 10 µM.³

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1. Bol, G.M., Vesuna, F., Xie, M., et al. Targeting DDX3 with a small molecule inhibitor for lung cancer therapy. EMBO Mol. Med. 7(5), 648-669 (2015).

2. Winnard, P.T., Jr., Vesuna, F., Bol, G.M., et al. Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment. Cancer Lett. 604, 217260 (2024).

3. Ciccosanti, F., Di Rienzo, M., Romagnoli, A., et al. Proteomic analysis identifies the RNA helicase DDX3X as a host target against SARS-CoV-2 infection. Antiviral Res. 190, 105064 (2021).