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.
ARN-3236 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HCT8
5 µM
24 hours
To evaluate the effect of ARN-3236 on cell survival after radiation, results showed that ARN-3236 significantly enhanced cell sensitivity to radiation.
MedComm (2020). 2025 Jan 28;6(2):e70083.
HCT116
5 µM
24 hours
To evaluate the effect of ARN-3236 on cell survival after radiation, results showed that ARN-3236 significantly enhanced cell sensitivity to radiation.
MedComm (2020). 2025 Jan 28;6(2):e70083.
SIK2-overexpressed HFLs (HFLs-SIK2)
0.5 µM
30 minutes
ARN-3236 inhibited SIK2 activity, reduced CRTC2 phosphorylation, and suppressed fibroblast differentiation and ECM expression.
BMC Pulm Med. 2022 Apr 11;22(1):140.
A2780
0.93 µM (IC50)
48 hours
ARN-3236 inhibited A2780 cell growth with an IC50 of 0.93 μM and increased nuclear-centrosome distance.
Clin Cancer Res. 2017 Apr 15;23(8):1945-1954.
SKOv3
1.23 µM (IC50)
72 hours
ARN-3236 inhibited SKOv3 cell growth with an IC50 of 1.23 μM.
Clin Cancer Res. 2017 Apr 15;23(8):1945-1954.
OVCAR8
1.56 µM (IC50)
96 hours
ARN-3236 enhanced paclitaxel sensitivity in OVCAR8 cells.
Clin Cancer Res. 2017 Apr 15;23(8):1945-1954.
OC316
1.63 µM (IC50)
96 hours
ARN-3236 enhanced paclitaxel sensitivity in OC316 cells.
Clin Cancer Res. 2017 Apr 15;23(8):1945-1954.
Mouse melanoma B16F0 cells
3 µM ARN 3236 or 1 µM YKL 06-061
72 hours
To investigate the inhibitory effect of Yakuchinone A on SIK inhibitor-induced melanogenesis. Results showed that Yakuchinone A inhibited melanin production in SIK inhibitor-activated B16F0 cells.
Int J Biol Sci. 2024 Jan 1;20(1):312-330
ARN-3236 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression
Intraperitoneal injection
1, 3, 10, 30, 60 mg/kg
Daily for 2 weeks
ARN-3236 exhibited significant antidepressant-like effects in both CSDS and CUMS models, accompanied by fully preventing stress-enhanced SIK2 expression and cytoplasmic translocation of CRTC1 in the hippocampus. ARN-3236 treatment also completely reversed the down-regulating effects of CSDS and CUMS on the hippocampal BDNF system and neurogenesis.
To evaluate the effect of ARN-3236 on radiotherapy efficacy, results showed that ARN-3236 significantly enhanced the inhibitory effect of radiotherapy.
MedComm (2020). 2025 Jan 28;6(2):e70083.
Nude mice
SKOv3ip and OVCAR8 xenograft models
Oral
60 mg/kg
Once daily for 7 days
ARN-3236 enhanced the antitumor effect of paclitaxel in SKOv3ip and OVCAR8 xenograft models.
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