Go 6976 is a potent inhibitor of protein kinases (PKs), with IC50 values of 0.02µM, 6.2µM, and 5.8µM for PKC, cGMP-dependent protein kinase, and myosin light-chain kinase, respectively[1]. Go 6976 blockes neurotrophin-induced signaling and autophosphorylation of neurotrophin-specific tyrosine kinase receptors[2]. Go 6976 has been widely used as an anticancer agent to inhibit FLT3 kinase activity and block leukemic cell growth[3].
In vitro, Go 6976 treatment at 100nM for 48 hours significantly inhibited the invasion of T24 cells[4]. Treatment of 5637 cells with 1µM Go 6976 for 24 hours significantly promoted apoptotic cell death and induced asynchronous cell mitosis[5]. Treatment with 300µM of Go 6976 for 1 hour reversed hyperglucose-induced insulin resistance in adipocytes[6].
In vivo, Go 6976 treatment via intraperitoneal injection at a single dose of 2.5mg/kg 30min before lipopolysaccharide (LPS)/D-galactosamine (d-GalN) administration improved mouse survival and alleviated liver injury[7]. Intraperitoneal injection of Go 6976 at a dose of 2mg/kg/day for 1 week significantly improved renal injury and reduced the area of fibrosis in a mouse model of unilateral ureteral obstruction (UUO)[8].
References:
[1] Qatsha K A, Rudolph C, Marmé D, et al. Gö 6976, a selective inhibitor of protein kinase C, is a potent antagonist of human immunodeficiency virus 1 induction from latent/low-level-producing reservoir cells in vitro[J]. Proceedings of the National Academy of Sciences, 1993, 90(10): 4674-4678.
[2] Behrens M M, Strasser U, Choi D W. Gö 6976 Is a Potent Inhibitor of Neurotrophin‐Receptor Intrinsic Tyrosine Kinase[J]. Journal of neurochemistry, 1999, 72(3): 919-924.
[3] Yoshida A, Zokumasu K, Ueda T. Go6976, a Potent FLT3 Kinase Inhibitor, Exerts Antiproliferative Activity Against Acute Myeloid Leukemia Via Inhibition Of Survivin and Mcl-1 In The Presence Of Human Serum[J]. Blood, 2013, 122(21): 3839.
[4] Koivunen J, Aaltonen V, Koskela S, et al. Protein kinase C α/β inhibitor Go6976 promotes formation of cell junctions and inhibits invasion of urinary bladder carcinoma cells[J]. Cancer research, 2004, 64(16): 5693-5701.
[5] Aaltonen V, Koivunen J, Laato M, et al. PKC inhibitor Go6976 induces mitosis and enhances doxorubicin-paclitaxel cytotoxicity in urinary bladder carcinoma cells[J]. Cancer letters, 2007, 253(1): 97-107.
[6] Robinson K A, Hegyi K, Hannun Y A, et al. Go-6976 reverses hyperglycemia-induced insulin resistance independently of cPKC inhibition in adipocytes[J]. Plos one, 2014, 9(10): e108963.
[7] Duan G J, Zhu J, Xu C Y, et al. Protective effect of Gö6976, a PKD inhibitor, on LPS/d-GalN-induced acute liver injury in mice[J]. Inflammation research, 2011, 60(4): 357-366.
[8] Xue X, Ren J, Sun X, et al. Protein kinase Cα drives fibroblast activation and kidney fibrosis by stimulating autophagic flux[J]. Journal of Biological Chemistry, 2018, 293(28): 11119-11130.
Go 6976 是一种有效的蛋白激酶(PKs)抑制剂，对PKC、cGMP依赖性蛋白激酶和肌球蛋白轻链激酶的IC50值分别为0.02µM、6.2µM和5.8µM[1]。Go 6976能阻断神经营养因子诱导的信号传导以及神经营养因子特异性酪氨酸激酶受体的自磷酸化[2]。Go 6976 已被广泛用作抗癌剂，以抑制FLT3激酶活性并阻断白血病细胞生长[3]。
在体外，用100nM的Go 6976处理T24细胞48小时能显著抑制细胞侵袭[4]。用1µM的Go 6976处理5637细胞24小时，能显著促进细胞凋亡性死亡并诱导非同步有丝分裂[5]。用300µM的Go 6976处理脂肪细胞1小时，可逆转高糖诱导的胰岛素抵抗[6]。
在体内，于注射脂多糖(LPS)/D-半乳糖胺(d-GalN)前30分钟，单次腹腔注射2.5mg/kg剂量的Go 6976，能提高小鼠存活率并减轻肝损伤[7]。在小鼠单侧输尿管梗阻(UUO)模型中，以2mg/kg/day的剂量腹腔注射Go 6976一周，能显著改善肾损伤并减少纤维化面积[8]。