ERBB-2 ONCOGENE INHIBITION BY GELDANAMYCIN DERIVATIVES - SYNTHESIS, MECHANISM OF ACTION, AND STRUCTURE-ACTIVITY-RELATIONSHIPS

Overexpression of the erbB-2 oncogene has been linked to poor prognosi s in breast, ovarian, and gastric cancers. Naturally occurring benzoqu inoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihy drogeldanamycin were found to potently deplete p185, the erbB-2 oncopr otein, in human breast cancer SKBR-3 cells in culture. Chemistry effor ts to modify selectively the ansa ring of GDM afforded derivatives wit h greater potency in, vitro and in vivo. Analogs demonstrated inhibiti on 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 withou t 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 pos itions was permitted. Structure-activity relationships are described f or 1-5-, 7-9-, 11-, 15-, and 22-substituted geldanamycins.