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Identification of a Geldanamycin Dimer That Induces the Selective Degradation of HER-Family Tyrosine Kinases¹

Program in Cell Biology, Department of Medicine [F. F. Z., G. C., P. N. M., L. S-L., N. R.], and Laboratory of Bioorganic Chemistry, Molecular Pharmacology Program [S. D. K., S. J. D.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

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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