生物活性

• 描述The epidermal growth factor receptor (EGF-R) is a tyrosine kinase transmembrane protein that is overexpressed by many epithelial malignancies, including transitional cell and renal cell carcinoma. Ligand-induced stimulation of cell growth depends on activation of the tyrosine kinase activity of the EGF-R. AG 555 is tyrphostin that have been shown to preferentially inhibit the EGF-R tyrosine kinase and thus may inhibit EGF-R-dependent cell growth^[1]. Non-cytotoxic doses of tyrphostin derivatives (AG-555, AG-18) blocked or substantially reduced Mo-MuLV replication in acute or chronically infected NIH/3T3 cellsA Esther,et al. Inhibition of Moloney murine leukemia virus replication by tyrphostins, tyrosine kinase inhibitors|FEBS Lett.1994 Mar 14;341(1):99-103.|https://pubmed.ncbi.nlm.nih.gov/8137930/. Three tyrphostins with the potency ratio AG555 >> AG18 >> AG814 were found to arrest growth with no adverse cytotoxic effects. The potency ratio to inhibit keratinocyte proliferation follows their potency to inhibit EGF receptor kinase activity in vitro^[2]. AG 555 selectively interferes with viral transcription in bovine papillomavirus type 1 (BPV-1)-transformed fibroblasts and induces suppression of cyclin-dependent kinase activity and cell cycle arrest. AG 555 treatment also led to an activation of the mitogen-activated protein kinase pathway by enhancing phosphorylation of JNK and p38. Increased JNK and p38 activity resulted in higher phosphorylation of the AP-1 family members c-Jun and activating transcription factor 2^[3]. The growth of HPV 16-immortalized human keratinocytes can be blocked by a selective EGF-R inhibitor, AG 1478, and by AG 555, a blocker of cyclin-dependent kinase 2 (Cdk2) activation. AG 1478 induces a massive increase in the Cdk2 protein inhibitors p27 and p21, whereas AG 555 inhibited the activation of Cdk2. Growth arrest induced by AG 1478 and AG 555 is accompanied by up to 20% of cells undergoing apoptosis^[4].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00307866	Hepatic Neoplasms	Phase 3	Completed	-	Italy ... more >> Bari, BA, Italy, 70124 Bologna, BO, Italy, 40100 Brescia, BS, Italy, 25123 Firenze, FI, Italy, 50100 Genova, GE, Italy, 16132 Milano, MI, Italy, 20132 Milano, MI, Italy, 20142 Milano, MI, Italy Palermo, PA, Italy Pisa, PI, Italy, 56126 Sassari, SS, Italy, 07100 Torino, TO, Italy, 10154 Trieste, TS, Italy, 34149 Verona, VE, Italy, 37134 Chieti, Italy, 66100 L'Aquila, Italy, 67100 Roma, Italy, 00144 Roma, Italy, 00161 Udine, Italy, 33100 Collapse <<

• 参考文献

• [1] N Sion-Vardy,et al. Antiproliferative effects of tyrosine kinase inhibitors (tyrphostins) on human bladder and renal carcinoma cells. J Surg Res. 1995 Dec;59(6):675-80.

  [2] H Ben-Bassat,et al. Tyrphostins suppress the growth of psoriatic keratinocytes. Exp Dermatol. 1995 Apr;4(2):82-8.

  [3] Sabine Baars,et al. Tyrphostin AG 555 inhibits bovine papillomavirus transcription by changing the ratio between E2 transactivator/repressor function. J Biol Chem. 2003 Sep 26;278(39):37306-13.

  [4] H Ben-Bassat,et al. Inhibitors of epidermal growth factor receptor kinase and of cyclin-dependent kinase 2 activation induce growth arrest, differentiation, and apoptosis of human papilloma virus 16-immortalized human keratinocytes. Cancer Res. 1997 Sep 1;57(17):3741-50.