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.