Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives

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.

Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90

“…In an effort to synthesize water-soluble analogs of 17-AAG, it was recognized that the benzoquinone of 17-AAG could be chemically reduced to its hydroquinone analog. Literature precedence suggested hydroquinone derivatives of geldanamycin were prone to air oxidation and readily converted back to their quinone forms (17,18). However, it was realized that protonation of the aniline nitrogen of 17-AAG hydroquinone decreases electron density in the aromatic ring, thus reducing the oxidative potential of the hydroquinone (Fig.…”

Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone

“…Geldanamycin has limited clinical potential due to its liver toxicity (Supko et al, 1995). However, the analogue 17-allylamino-17-demethoxygeldanamycin (17-AAG) has reduced liver toxicity but retains the potent antitumour activity of the parent compound (Schulte and Neckers, 1998;Schnur et al, 1995). This derivative has very recently entered phase I clinical trial at our centre and in the USA under the auspices of the US National Cancer Institute and the UK Cancer Research Campaign.…”

A pair of sulfur-containing geldanamycin analogs, 19-S-methylgeldanamycin and 4,5-dihydro- 19-S-methylgeldanamycin, from Streptomyces hygroscopicus 17997

“…Some hindered amines could also undergo addition reaction in vitro at C19-of GDM nonenzymatically. 7,8 Several sulfur-containing ansamycins, such as thiazinotrienomycin, trierixin, 3-methylthiorifamycin SV and thiazorifamycins, naphthomycins I and J, and awamycin [23][24][25][26][27][28] had been isolated from Micromonospora sp. or Streptomyces sp.…”