AS601245 is a potent ATP-competitive JNK inhibitor with IC50 values of 0.15µM, 0.22, and 0.07µM for JNK1, JNK2, and JNK3, respectively [1]. AS601245 can prevent P-TEFb from being released from the inactive complex formed with HEXIM-1, and interfere with the reactivation of the HIV-1 virus at multiple levels[2]. AS601245 has been widely used to inhibit the growth of follicular cells and interfere with the progression of the cell cycle[3].
In vitro, AS601245 treatment for 96h significantly inhibited the proliferation of CaCo-2 cells, with an IC50 value of 2.5µM[4]. 0.1µM of AS601245 treatment for 24 hours significantly increased the expression of p21 in HepG2 cells and inhibited cell viability[5]. Treatment with 10µM AS601245 for 24 hours significantly promoted apoptosis of SH-SY5Y cells, accompanied by an increase in caspase-3 activity, expression of pro-apoptotic proteins, as well as significant disruptions in oxidative phosphorylation and glycolysis[6].
In vivo, AS601245 treatment via intraperitoneal injection at a dose of 80mg/kg at 15 minutes and 24 hours after restoration of carotid artery flow prevented neurite loss, reduced astrogliosis, and improved long-term memory deficits induced by cerebral ischemia in gerbils [7]. A single oral administration of 10mg/kg dose of AS601245 significantly inhibited the release of TNF-α in mice caused by endotoxins[8].
References:
[1] Malemud C J. Small molecular weight inhibitors of stress-activated and mitogen-activated protein kinases[J]. Mini Reviews in Medicinal Chemistry, 2006, 6(6): 689-698.
[2] Wolschendorf F, Bosque A, Shishido T, et al. Kinase control prevents HIV-1 reactivation in spite of high levels of induced NF-κB activity[J]. Journal of virology, 2012, 86(8): 4548-4558.
[3] Oktem O, Oktay K. c-Jun N-terminal kinase (JNK) pathway controls granulosa cell mitosis: a novel mechanism in regulation of preantral follicle growth[J]. Fertility and Sterility, 2008, 90: S330.
[4] Cerbone A, Toaldo C, Minelli R, et al. Rosiglitazone and AS601245 decrease cell adhesion and migration through modulation of specific gene expression in human colon cancer cells[J]. PLoS One, 2012, 7(6): e40149.
[5] Cerbone A, Toaldo C, Pizzimenti S, et al. AS601245, an anti‐inflammatory JNK inhibitor, and Clofibrate have a synergistic effect in inducing cell responses and in affecting the gene expression profile in CaCo‐2 colon cancer cells[J]. PPAR research, 2012, 2012(1): 269751.
[6] Granek Z, Siwecka N, Saramowicz K, et al. Pharmacological Inhibition of JNK Signalling Exerts Anti-Neoplastic Effects on SH-SY5Y Human Neuroblastoma Cells[J]. International Journal of Molecular Sciences, 2025, 26(24): 11894.
[7] Carboni S, Boschert U, Gaillard P, et al. AS601245, ac‐Jun NH2‐terminal kinase (JNK) inhibitor, reduces axon/dendrite damage and cognitive deficits after global cerebral ischaemia in gerbils[J]. British journal of pharmacology, 2008, 153(1): 157-163.
[8] Carboni S, Hiver A, Szyndralewiez C, et al. AS601245 (1, 3-Benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) Acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties[J]. The Journal of pharmacology and experimental therapeutics, 2004, 310(1): 25-32.
AS601245是一种强效的ATP竞争性JNK抑制剂，对JNK1、JNK2和JNK3的IC50值分别为0.15µM、0.22µM和0.07µM[1]。AS601245可阻止P-TEFb从与HEXIM-1形成的非活性复合物中释放，并在多个水平上干扰HIV-1病毒的再激活[2]。AS601245已被广泛用于抑制滤泡细胞的生长并干扰细胞周期的进程[3]。
在体外，AS601245处理CaCo-2细胞96小时，显著抑制了细胞增殖，IC50值为2.5µM[4]。0.1µM的AS601245处理HepG2细胞24小时，显著增加了p21的表达并抑制了细胞活力[5]。10µM的AS601245 处理SH-SY5Y细胞24小时，显著促进了细胞凋亡，同时伴随着caspase-3活性、促凋亡蛋白表达的增加，以及氧化磷酸化和糖酵解的显著破坏[6]。
在体内，在沙鼠颈动脉血流恢复后15分钟和24小时分别腹腔注射80mg/kg剂量的AS601245，可防止神经突丢失，减少星形胶质细胞增生，并改善脑缺血引起的长期记忆缺陷[7]。单次口服10mg/kg剂量的AS601245显著抑制endotoxins引起的小鼠体内TNF-α释放[8].