ARN-3236

ARN3236 is an inhibitor of salt-inducible kinase 2 (SIK2; IC₅₀ = <1 nM).¹ It is selective for SIK2 over SIK1 and SIK3 (IC₅₀s = 21.63 and 6.63 nM, respectively). It inhibits TNF-α secretion in RAW 264.7 cells (IC₅₀ = ~2.5 ?M) and reduces phosphorylation of the SIK2 targets CRTC3 and HDAC4 in macrophages when used at a concentration of 3 ?M. ARN3236 inhibits growth of 10 ovarian cancer cell lines (IC₅₀s = 0.8-2.6 ?M) and increases the sensitivity of eight of them to paclitaxel .² It halts the cell cycle at the G₂/M phase and induces apoptosis and tetraploidy in SKOV3 cells when used at a concentration of 1 ?M. ARN3236 (60 mg/kg per day) has an additive effect on reducing tumor growth when used in combination with paclitaxel in an ovarian cancer mouse xenograft model.

1.Lombardi, M.S., Gilliéron, C., Dietrich, D., et al.SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotypeJ. Leukoc. Biol.99(5)711-721(2016) 2.Zhou, J., Alfraidi, A., Zhang, S., et al.A novel compound ARN-3236 inhibits salt-inducible kinase 2 and sensitizes ovarian cancer cell lines and xenografts to paclitaxelClin. Cancer Res.23(8)1945-1954(2017)