Identification of a geldanamycin dimer that induces the selective degradation of HER-family tyrosine kinases Journal Article
| Authors: | Zheng, F. F.; Kuduk, S. D.; Chiosis, G.; Münster, P. N.; Sepp-Lorenzino, L.; Danishefsky, S. J.; Rosen, N. |
| Article Title: | Identification of a geldanamycin dimer that induces the selective degradation of HER-family tyrosine kinases |
| 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. |
| Keywords: | immunohistochemistry; human tissue; human cell; cell division; gene overexpression; apoptosis; breast cancer; enzyme degradation; down-regulation; tumor cells, cultured; protein tyrosine kinase; drug synthesis; breast neoplasms; receptor, igf type 1; blotting, western; substrate specificity; quinones; dimerization; receptor, erbb-2; receptors, estrogen; catalysis; antibiotics, antineoplastic; inhibitory concentration 50; steroid receptor; drug binding; benzoquinones; lactams, macrocyclic; geldanamycin; proto-oncogene proteins c-raf; antimicrobial activity; ansamycin derivative; herbimycin a; protein serine kinase; humans; human; priority journal; article |
| Journal Title: | Cancer Research |
| Volume: | 60 |
| Issue: | 8 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2000-04-15 |
| Start Page: | 2090 |
| End Page: | 2094 |
| Language: | English |
| PUBMED: | 10786665 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
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