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.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. zhengf@mskcc.org
authors.forename: F F
authors.initials: FF
authors.lastname: Zheng
authors.forename: S D
authors.initials: SD
authors.lastname: Kuduk
authors.forename: G
authors.initials: G
authors.lastname: Chiosis
authors.forename: P N
authors.initials: PN
authors.lastname: Münster
authors.forename: L
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: S J
authors.initials: SJ
authors.lastname: Danishefsky
authors.forename: N
authors.initials: N
authors.lastname: Rosen
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016227:Benzoquinones; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D019281:Dimerization; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D019908:Proto-Oncogene Proteins c-raf; D011809:Quinones; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011960:Receptors, Estrogen; C001277:geldanamycin