Geldanamycin: the prototype of a class of antitumor drugs targeting the heat shock protein 90 family of molecular chaperones.

Abstract

Despite tremendous advances in basic and clinical oncology, the prognosis for most patients with neoplastic diseases is still dismal. Therefore, new therapeutic strategies must be sought. A novel drug for the treatment of malignant diseases should have a mechanism of action different from those known for established oncological therapeutics. In addition, it is desirable to attempt to relate the antitumor activity of a candidate compound with molecular effects on proteins relevant for the pathogenesis of malignant diseases. Geldanamycin (GA; NSC 122750) has the potential to fulfill the aforementioned criteria. It was first purified in 1970 from the broth of Streptomyces hygroscopicus var geldanus var nova (DeBoer et al 1970). As a benzoquinone ansamycin (BA), it consists of a quinone ring and a hydrophobic ansa bridge (Fig 1; Rinehart and Shield 1976). The DNA sequences responsible for GA biosynthesis have been previously characterized (Allen and Ritchie 1994). The antineoplastic effect of GA was already noted in its first description (DeBoer et al 1970). Fig. 1. Structural formula of geldanamycin Molecular studies revealed the binding of GA to members of the heat shock protein 90 (Hsp90) family of molecular chaperones (Whitesell et al 1994). Interference with the function of these Hsps seems to be the major mechanism of action of GA. This review focuses on oncological aspects and will not deal with other biological activities of GA, such as its virucidal (Li et al 1977) or ischemia protective (Conde et al 1997) effects.