Description
AG-879 (148741-30-4) inhibits NGF-induced neurite growth in PC12 cells via selective inhibition of NGF receptor(pp140c-trk) autophosphorylation (IC50 = 10 μM). No inhibition of EGF, or PDGF receptor phosphorylation is observed at typical working concentrations.
Uses
Tyrphostin AG 879 is a dual EGFR/HER2 inhibitor that was administered together with androgen withdrawal therapy and was shown to sensitize prostate cancer cells to apoptosis.
Definition
ChEBI: 3-amino-2-[(3,5-ditert-butyl-4-oxo-1-cyclohexa-2,5-dienylidene)methyl]-3-mercapto-2-propenenitrile is a monoterpenoid.
Biological Activity
AG-879, a member of the tyrphostin family of tyrosine kinase inhibitors, inhibits NGF receptor (pp140c-trk) autophosphorylation selectively with no inhibition of EGF or PDGF receptor phosphorylation (IC50=10 μM). AG-879 inhibits NGF-induced neurite outgrowth in PC12 cells.
in vitro
ag 879 has been widely used as a tyr kinase inhibitor specific for erbb2 and flk-1, a vegf receptor. the ic50 value for erbb2 and flk-1 was approximately 1 μm. ag 879 at 10 nm blocked the specific interaction between the tyr-kinase etk and pak1 (a cdc42/rac-dependent ser/thr kinase) in cell culture. ag 879 (10 nm) showed no inhibitory effects on the purified etk and pak1 directly in vitro, suggesting that this drug blocked the etk-pak1 pathway by targeting the highly sensitive kinase upstream of etk. src was insensitive to ag 879. fak was inhibited by 100 nm ag 879, but not by 10 nm ag879 [2]. ag 879 inhibited proliferation of human breast cancer cells through an effect involving inhibition of map kinase activation. ag 879 markedly inhibited the expression of the raf-1 gene, which encoded an upstream mapkkk. additionally, ag 879 inhibited the expression of her-2[3]. treatment with ag879 (20 μm) dramatically decreased proliferation with a variable increase in apoptosis in cell lines from human leiomyosarcoma (htb-114, htb-115, htb-88), rhabdomyosarcoma (htb-82, te-671), prostatic adenocarcinoma (pc-3), acute promyelocytic leukemia (hl-60) and histiocytic lymphoma (u-937) [4].
in vivo
in athymic nod/scid mice grafted with htb-114 or hl-60, administration of ag879 at 2 mg induced a decrease in cancer growth [4]. ag 879 administration (20 mg/kg) kept 50% of mice absolutely free of ras-induced sarcomas. in the nude mice carrying v-ha-ras transformed nih 3t3 cells, ag 879 dramatically reduced the size of the growing sarcomas [5].
References
1) Ohmichi et al. (1993), The tyrosine kinase inhibitor tyrphostin blocks the cellular actions of nerve growth factor; Biochemistry, 32 4650
