CCT020312 is a selective protein kinase R-like endoplasmic reticulum kinase (PERK) pathway agonist [1]. CCT020312 activates the endoplasmic reticulum stress (ER stress)-related unfolded protein response (UPR) pathway by promoting eIF2α phosphorylation and upregulating ATF4 expression, thereby inducing cell cycle arrest and autophagy [2-3]. CCT020312 is often used to study diseases such as tumors and neurodegenerative diseases [4].
In MDA-MB-453 and CAL-148 cells, CCT020312 (2-12μM; 24h, 48h) significantly inhibited cell viability in a dose-dependent manner [5]. In HT29 cells, CCT020312 (1-9μM; 24h) treatment effectively inhibited cell proliferation [6]. In HCT116 and SW480 cells, CCT020312 (0.625-50μM; 12h, 24h, 48h) exposure reduced the cell viability of cell in a time- and dose-dependent manner [7].
In nflammation-mediated osteoporosis (IMO) rat model, CCT020312 (1mg/kg, 2mg/kg; ip; 20d) significantly alleviated the osteoporosis symptoms of IMO rats by improving bone remodeling indicators, increasing bone density, promoting osteogenesis, and inhibiting bone resorption and inflammation [8]. In aged mice, activation of PERK with CCT020312 (2mg/kg; ip; single injection) increases the amount of GluN2A and GluN2B in synaptosomal preparations [9].
References:
[1]. Bruch J, Xu H, Rösler TW, et al. PERK activation mitigates tau pathology in vitro and in vivo. EMBO molecular medicine. 2017 Mar; 9(3): 371-384.
[2]. Stockwell SR, Platt G, Barrie SE, et al. Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. PloS one. 2012 Jan 12; 7(1): e28568.
[3]. Zhou D, Yin M, Kang B, et al. CCT020312 exerts anti-prostate cancer effect by inducing G1 cell cycle arrest, apoptosis and autophagy through activation of PERK/eIF2α/ATF4/CHOP signaling. Biochemical pharmacology. 2024 Mar 1; 221: 116038.
[4]. Talukdar G, Orr HT, Lei Z. The PERK pathway: beneficial or detrimental for neurodegenerative diseases and tumor growth and cancer. Human molecular genetics. 2023 Aug 15; 32(16): 2545-2557.
[5]. Li X, Yu X, Zhou D, et al. CCT020312 inhibits triple-negative breast cancer through PERK pathway-mediated G1 phase cell cycle arrest and apoptosis. Frontiers in Pharmacology. 2020 May 19; 11: 737.
[6]. Stockwell SR, Platt G, Barrie SE, et al. Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. PloS one. 2012 Jan 12; 7(1): e28568.
[7]. Lei Y, He L, Yan C, et al. PERK activation by CCT020312 chemosensitizes colorectal cancer through inducing apoptosis regulated by ER stress. Biochemical and biophysical research communications. 2021 Jun 11; 557: 316-322.
[8]. Tang BM, Li ZW, Wang ZY. PERK activator CCT020312 prevents inflammation-mediated osteoporosis in the ovariectomized rats. Gynecological Endocrinology. 2021 Apr 3; 37(4): 342-348.
[9]. Chen K, Hu Q, Gupta R, et al. Inhibition of unfolded protein response prevents post‐anesthesia neuronal hyperactivity and synapse loss in aged mice. Aging Cell. 2022 Apr; 21(4): e13592.
CCT020312是一种选择性蛋白激酶R样内质网激酶（PERK）通路激动剂 [1]。CCT020312通过促进eIF2α磷酸化和上调ATF4表达来激活内质网应激（ER stress）相关的未折叠蛋白反应（UPR）通路，从而诱导细胞周期停滞和自噬 [2-3]。CCT020312常用于研究肿瘤和神经退行性疾病等疾病 [4]。
在MDA-MB-453和CAL-148细胞中，CCT020312（2-12μM；24h，48h）以剂量依赖性方式显著抑制细胞活力 [5]。在HT29细胞中，CCT020312（1-9μM；24h）处理可有效抑制细胞增殖 [6]。在HCT116和SW480细胞中，CCT020312（0.625-50μM；12h，24h，48h）暴露以时间和剂量依赖性方式降低细胞活力 [7]。
在炎症介导的骨质疏松症（IMO）大鼠模型中，CCT020312（1mg/kg，2mg/kg；ip；20d）通过改善骨重建指标、增加骨密度、促进成骨、抑制骨吸收和炎症，显著缓解IMO大鼠的骨质疏松症状 [8]。在老年小鼠中，用CCT020312（2mg/kg；ip；单次注射）激活PERK可增加突触体制剂中GluN2A和GluN2B的含量 [9]。