Identification of a geldanamycin dimer that induces the selective degradation of HER-family tyrosine kinases

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2000-04, Vol.60 (8), p.2090-2094
Main Authors: ZHENG, F. F, KUDUK, S. D, CHIOSIS, G, MÜNSTER, P. N, SEPP-LORENZINO, L, DANISHEFSKY, S. J, ROSEN, N
Format: Article
Language:English
Subjects:
Antibiotics, Antineoplastic - chemistry
Antibiotics, Antineoplastic - pharmacology
Antibiotics, Antineoplastic - therapeutic use
Antineoplastic agents
Benzoquinones
Biological and medical sciences
Blotting, Western
Breast Neoplasms - drug therapy
Breast Neoplasms - enzymology
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Division - drug effects
Dimerization
Down-Regulation - drug effects
geldanamycin
General aspects
HER protein
Humans
Immunohistochemistry
Inhibitory Concentration 50
Lactams, Macrocyclic
Medical sciences
Pharmacology. Drug treatments
Proto-Oncogene Proteins c-raf - metabolism
Quinones - chemistry
Quinones - pharmacology
Quinones - therapeutic use
Receptor, ErbB-2 - antagonists & inhibitors
Receptor, ErbB-2 - biosynthesis
Receptor, ErbB-2 - metabolism
Receptor, IGF Type 1 - metabolism
Receptors, Estrogen - metabolism
Substrate Specificity
Tumor Cells, Cultured
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Summary: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.
ISSN:0008-5472
1538-7445