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 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.
Zheng
F F
FF
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. zhengf@mskcc.org
Kuduk
S D
SD
Chiosis
G
G
Münster
P N
PN
Sepp-Lorenzino
L
L
Danishefsky
S J
SJ
Rosen
N
N
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
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