ABSTRACT
The erbB-2 oncogene encodes a transmembrane protein tyrosine kinase which plays a pivotal role in signal transduction and has been implicated when overexpressed in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the quinoid moiety of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs 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). Specifically, dosed intraperitoneally at 100 mg/kg, 17-(allylamino)-17-demethoxygeldanamycin and other 17-amino analogs were effective at reducing p185 phosphotyrosine in subcutaneous flank FRE/erbB-2 tumors. Modifications to the 17-19-positions of the quinone ring revealed a broad structure-activity relationship in vitro.
Subject(s)
Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Quinones/chemistry , Quinones/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/metabolism , Benzoquinones , Breast Neoplasms/drug therapy , Dose-Response Relationship, Drug , Female , Humans , Lactams, Macrocyclic , Mice , Mice, Nude , Phosphotyrosine/metabolism , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinones/metabolism , Rats , Rifabutin/analogs & derivatives , Structure-Activity Relationship , Transfection , Tumor Cells, CulturedABSTRACT
Overexpression of the erbB-2 oncogene has been linked to poor prognosis in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the ansa ring of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs 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. Functional group modification in the ansa ring was performed stereoselectively and regiospecifically without the need for protection strategies. Essential functional groups that were required for anti-erbB-2 activity were the 7-carbamate and the 2,3-double bond. Modification of the functional groups at the other positions was permitted. Structure-activity relationships are described for 1-5-, 7-9-, 11-, 15-, and 22-substituted geldanamycins.
