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  • Title: Identification of a geldanamycin dimer that induces the selective degradation of HER-family tyrosine kinases.
    Author: Zheng FF, Kuduk SD, Chiosis G, Münster PN, Sepp-Lorenzino L, Danishefsky SJ, Rosen N.
    Journal: Cancer Res; 2000 Apr 15; 60(8):2090-4. PubMed ID: 10786665.
    Abstract:
    Geldanamycin (GM) is a natural antibiotic that binds Hsp90 and induces the degradation of receptor tyrosine kinases, steroid receptors, and Raf. It is a potent inhibitor of cancer cells that overexpress HER-kinases, but its effects on other important proteins may cause significant toxicity and limit its clinical use. We report the synthesis and identification of a GM dimer, GMD-4c, which had selective activity against HER-kinases. Selectivity was a function of linker length and required two intact GM moieties. GMD-4c is a potent inducer of G1 block and apoptosis of breast cancer cell lines that overexpress HER2, but does not appreciably inhibit the growth of 32D cells that lack HER-kinases. GMD-4c could be useful in the treatment of carcinomas dependent on HER-kinases.
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