INHIBITION OF THE ONCOGENE PRODUCT P185(ERBB-2) IN-VITRO AND IN-VIVO BY GELDANAMYCIN AND DIHYDROGELDANAMYCIN DERIVATIVES

The erbB-2 oncogene encodes a transmembrane protein tyrosine kinase wh ich plays a pivotal role in signal transduction and has been implicate d when overexpressed in breast, ovarian, and gastric cancers. Naturall y occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamy cin (GDM), and dihydrogeldanamycin were found to potently deplete p185 , the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in cultu re. Chemistry efforts to modify selectively the quinoid moiety of GDM afforded derivatives with greater potency in vitro and in vivo. Analog s demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2 (FRE/erbB-2). Sp ecifically, dosed intraperitoneally at 100 mg/kg, 17-(allylamino)-17-d emethoxygeldanamycin and other 17-amino analogs were effective at redu cing p185 phosphotyrosine in subcutaneous flank FRE/erbB-2 tumors. Mod ifications to the 17-19-positions of the quinone ring revealed a broad structure-activity relationship in vitro.