ARN-3236 is a novel, the first orally available and selective SIK2 inhibitor which inhibits SIK2, SIK1 and SIK3 with IC50 values of <1nM, 21.63nM and 6.63nM, respectively. Inhibition of SIKs by ARN-3236 blocked TNF-α secretion with IC50 of ~2.5μM in RAW264.7 cells stimulated with LPS (whereas signs of cell toxicity with ARN-3236 at 30μM). Preincubation with ARN-3236 at 3μM significantly blocked TNF and induced IL-10 upon LPS stimulation in human macrophages. Also it decreased the production of IL-1β upon activation of TLR4 and TLR2 signaling, as well as induced a robust dephosphorylation of CRTC3 and HDAC4. Inhibition of SIK2, which regulates CREB1 activity via the phosphorylation of TORC2 and TORC3 and their sequestration in the cytoplasm, by ARN-3236 led to enhanced CREB1 activity in a dose- and time-dependent manner. For SIK2 is a centrosome kinase required for mitotic spindle formation and a potential target for ovarian cancer therapy, inhibition of SIK2 by ARN-3236 inhibited growth of 10 ovarian cancer cell lines (ES2, SKOv3, OVCAR3, A2780, HEY, OC316, IGROV1, UPN251, OVCAR8, OVCAR5) with IC50s of 0.8-2.6μM and enhanced sensitivity to paclitaxel both in vitro and in vivo. It uncoupled the centrosome from the nucleus in interphase, blocked centrosome separation in mitosis, caused prometaphase arrest and induced apoptotic cell death and tetraploidy. ARN-3236 also inhibited AKT phosphorylation and attenuated survivin expression. Oral administration of ARN-3236 at a dose of 60mg/kg/day daily for 7 days enhanced sensitivity to paclitaxel in SKOv3ip and OVCAR8 xenografts.
作用机制
ARN-3236 competes with ATP binding to SIK2 protein and inhibits SIK2 kinase activity.
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