Cell lines

MCF-7 cells, MDA-MB-231 cells, SK-BR-3 cells, 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)

Preparation method

Soluble in DMSO >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

20 μM, 24 h

Applications

In MCF-7 cells, AG 879 dose-dependently reduced cell numbers and showed a significant effect at 0.4 μM. AG 879 showed a potent effect on MDA-MB-231 cells and SK-BR-3 cells. Treatment with AG 879 for 24 h inhibited activation of ERK-1/2. AG 879 markedly reduced cell numbers and mitotic figures. AG 879 (5 μM) significantly reduced levels of RAF-1 mRNA after 6 and 24 h treatment. AG 879 (5 μM) significantly reduced levels of HER-2 mRNA. AG 879 (20 μM) decreased HER-2 mRNA levels in overexpressing SK-BR-3 cells. 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).

Animal models

Athymic NOD/SCID mice grafted with HTB-114 or HL-60, Nude mice carrying v-Ha-RAS transformed NIH 3T3 cells

Dosage form

Subcutaneous injection

Application

Treatment with AG879 (2 mg) in immunodepressed mice grafted with leiomyosarcoma or promyelocytic leukemia cells (HTB-114 or HL-60) resulted in dramatic reductions in tumor sizes. AG 879(20 mg/kg) treatment kept 50% of mice absolutely free of RAS-induced sarcomas, and dramatically reduced the size of the growing sarcomas in the nude mice carrying v-Ha-RAS transformed NIH 3T3 cells.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Tyrphostin AG879 is a tyrosine kinase inhibitor that inhibits the phosphorylation of TrKA, but not TrKB and TrKC. Tyrphostin AG879 is also a ErbB2 kinase inhibitor, has at least 500-fold higher selectivity to ErbB2 than EGFR (IC50 >500 μmol/L). The IC50 of tyrphostinAG879 against ErbB2 is 1 μmol/L [1].

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].  Levitzki A1,Gazit A. Tyrosine kinase inhibition: an approach to drug development.Science.1995 Mar 24;267(5205):1782-8.
[2].  He H1,Hirokawa Y,Gazit A,Yamashita Y,Mano H,Kawakami Y,Kawakami,Hsieh CY,Kung HJ,Lessene G,Baell J,Levitzki A,Maruta H. The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and malignant transformation.Cancer Biol Ther.2004 Jan;3(1):96-101. Epub 2004 Jan 29.
[3].  Larsson LI1. Novel actions of tyrphostin AG 879: inhibition of RAF-1 and HER-2 expression combined with strong antitumoral effects on breast cancer cells.Cell Mol Life Sci.2004 Oct;61(19-20):2624-31.
[4].  Rende M1,Pistilli A,Stabile AM,Terenzi A,Cattaneo A,Ugolini G,Sanna P.
Role of nerve growth factor and its receptors in non-nervous cancer growth: efficacy of a tyrosine kinase inhibitor (AG879) and neutralizing antibodies antityrosine kinase receptor A and antinerve growth factor: an in-vitro and in-vivo study. Anticancer Drugs.2006 Sep;17(8):929-41.
[5].  He H1,Hirokawa Y,Manser E,Lim L,Levitzki A,Maruta H. Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation.Cancer J.2001 May-Jun;7(3):191-202.