ARN-3236 is a selective salt-inducible kinase 2 (SIK2) inhibitor with an IC50 of less than 1nM. ARN-3236 also inhibits the activity of SIK1 (IC50<21.63nM) and SIK3 (IC50<6.63nM)[1-2]. By inhibiting SIK2 activity, ARN-3236 blocks centrosome separation, induces cell cycle arrest and apoptosis. ARN-3236 is used in research related to cancer and neuroprotection[3-4].
In vitro, colorectal cancer cells were pretreated with ARN-3236 (5–10µM) for 24 hours and subsequently irradiated with X-rays (2–6Gy). ARN-3236 significantly enhanced cellular radiosensitivity and increased radiation-induced growth inhibition and apoptosis. ARN-3236 dose-dependently reduced the efficiency of homologous recombination repair by inhibiting SIK2 kinase activity[5]. SKOv3, OVCAR8, and other ovarian cancer cells were pretreated with ARN-3236 (0.6–2µM) for 24 hours, followed by treatment with paclitaxel (0–25µM) for 72 hours. By inhibiting SIK2 kinase activity, ARN-3236 blocked centrosome separation and attenuated the AKT/survivin signaling pathway, thereby significantly enhancing the cytotoxicity of paclitaxel while inducing G2/M phase arrest and apoptosis[6].
In vivo, a pulmonary fibrosis model was established in BALB/C mice via intratracheal instillation of bleomycin (5 mg/kg). Starting on the day of modeling, the mice received a daily intraperitoneal injection of ARN-3236 (10–3mg/kg) for 28 days. ARN-3236 dose-dependently alleviated bleomycin-induced body weight loss and increased lung coefficient. ARN-3236 reduced hydroxyproline content, collagen deposition, and the expression of α-smooth muscle actin (α-SMA) and type I collagen (COL1A) in lung tissue, thereby significantly mitigating bleomycin-induced pulmonary fibrosis[7]. A depression model was induced in C57BL/6J mice using chronic social defeat stress (CSDS) or chronic unpredictable mild stress (CUMS). Starting at the end of the stress induction, the mice received a daily intraperitoneal injection of ARN-3236 (10–60mg/kg) for 2 weeks. ARN-3236 ameliorated CSDS-induced social avoidance behavior and produced significant antidepressant-like effects[8].
References:
[1] Lombardi MS, Gilliéron C, Dietrich D, et al. SIK inhibition in human myeloid cells modulates TLR and IL-1R signaling and induces an anti-inflammatory phenotype. J Leukoc Biol. 2016 May;99(5):711-21.
[2] Bon H, Wadhwa K, Schreiner A, et al. Salt-inducible kinase 2 regulates mitotic progression and transcription in prostate cancer. Mol Cancer Res. 2015 Apr;13(4):620-635.
[3] Rong Z, Zhang L, Li Z, et al. SIK2 maintains breast cancer stemness by phosphorylating LRP6 and activating Wnt/β-catenin signaling. Oncogene. 2022 Apr;41(16):2390-2403.
[4] Fang N, Wang Y, Chen Y, et al. SIK2 mediated mitochondrial homeostasis in spinal cord injury: modulating oxidative stress and the AIM2 inflammasome via CRTC1/CREB signaling. J Neuroinflammation. 2025 Dec 3;22(1):283.
[5] Meng Y, Li S, Lu DS, et al. Salt-inducible kinase 2 confers radioresistance in colorectal cancer by facilitating homologous recombination repair. MedComm (2020). 2025 Jan 28;6(2):e70083.
[6] 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 Paclitaxel. Clin Cancer Res. 2017 Apr 15;23(8):1945-1954.
[7] Zou L, Hong D, Li K, et al. Salt-inducible kinase 2 (SIK2) inhibitor ARN-3236 attenuates bleomycin-induced pulmonary fibrosis in mice. BMC Pulm Med. 2022 Apr 11;22(1):140.
[8] Liu Y, Tang W, Ji C, et al, The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway. Front Pharmacol. 2021 Jan 14;11:624429.
ARN-3236是一种选择性盐诱导激酶2（SIK2）抑制剂（IC50<1nM）。ARN-3236也可抑制SIK1（IC50<21.63nM）和SIK3（IC50<6.63nM）的活性[1-2]。ARN-3236通过抑制SIK2活性来阻断中心体分离、诱导细胞周期停滞和凋亡。ARN-3236 6可用于癌症以及神经保护的相关研究[3-4]。
在体外，ARN-3236（5–10µM）预处理结直肠癌细胞24小时，随后进行X射线（2–6Gy）照射。ARN-3236可显著增强细胞的放射敏感性，同时增加辐射诱导的生长抑制和凋亡。ARN-3236通过抑制SIK2激酶活性，剂量依赖性地降低同源重组修复效率[5]。ARN-3236（0.6–2µM）预处理SKOv3、OVCAR8等卵巢癌细胞24小时，随后以紫杉醇（0–25µM）处理72小时。ARN-3236通过抑制SIK2激酶活性，阻断中心体分离并减弱AKT/survivin信号通路，显著增强紫杉醇的细胞毒性，同时诱导G2/M期阻滞、凋亡[6]。
在体内，ARN-3236（10–30mg/kg）每天一次腹腔注射，用于处理经博来霉素（5mg/kg）诱导的肺纤维化模型BALB/C小鼠，从造模当天开始持续28天。ARN-3236剂量依赖性地减轻了博来霉素引起的体重下降和肺系数升高，减少了肺组织中羟脯氨酸含量、胶原沉积以及α-平滑肌动蛋白（α-SMA）和I型胶原（COL1A）的表达，显著减轻了博来霉素诱导的肺纤维化[7]。ARN-3236（10–60mg/kg）每天一次腹腔注射，用于处理经慢性社交挫败应激（CSDS）或慢性不可预知温和应激（CUMS）诱导的抑郁模型C57BL/6J小鼠，从应激造模结束后开始持续2周。ARN-3236改善了CSDS引起的社交回避行为，产生了显著的抗抑郁样作用[8]。