Information ARN-3236 ARN-3236 is a potent, orally available and selective inhibitor of salt-inducible kinase 2 (SIK2) with IC50 of <1 nM, 21.63 nM and 6.63 nM for SIK2, SIK1 and SIK3, respectively. ARN-3236 induces apoptosis in cancer cells.
Targets SIK2 (Cell-free assay); SIK3 (Cell-free assay); SIK1 (Cell-free assay) 1 nM; 6.63 nM; 21.63 nM
In vitro SIK2 is overexpressed in approximately 30% of high grade serous ovarian cancers. ARN-3236 inhibits growth of 10 ovarian cancer cell lines at an IC50 of 0.8 to 2.6 μM, where the IC50 of ARN-3236 is inversely correlated with endogenous SIK2 expression (Pearson’s r = −0.642, P = 0.03). ARN-3236 enhances sensitivity to paclitaxel in 8 of 10 cell lines. In at least three cell lines a synergistic interaction is observed. ARN-3236 uncouples the centrosome from the nucleus in interphase, blocks centrosome separation in mitosis, causes prometaphase arrest and induces apoptotic cell death and tetraploidy. ARN-3236 also inhibits AKT phosphorylation and attenuates survivin expression.
In vivo The antitumor activity of ARN-3236 is measured using ovarian cancer xenograft model in nu/nu mice. In SKOv3ip xenograft model, ARN-3236 plus paclitaxel produces greater inhibition of tumor growth than any other group and showed statistically significant difference compared to paclitaxel alone (P = 0.028). ARN-3236 also inhibits SIK2 activity and enhances paclitaxel sensitivity in OVCAR8 xenografts.
Cell Research(from reference) Cell lines：HEY, A2780, UPN251, OVCAR3, OVCAR5, OVCAR8, ES-2, OC316, SKOv3 and IGROV1 Concentrations：1 μM, 2 μM, 3 μM, 5 μM Incubation Time：16 h, 24 h, 32 h, 48 h | 
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