Geldanamycin and its anti-cancer activities.

Geldanamycin is a benzoquinone ansamycin antibiotic that manifests anti-cancer activity through the inhibition of HSP90-chaperone function. The HSP90 molecular chaperone is expressed at high levels in a wide variety of human cancers including melanoma, leukemia, and cancers in colon, prostate, lung, and breast. In cancer cells dependent upon mutated and/or over-expressed oncogene proteins, HSP90 is thought to have a critical role in regulating the stability, folding, and activity of HSP90-associated proteins, so-called "client proteins". These client proteins include the growth-stimulating proteins and kinases that support malignant transformation. Recently, oncogenic activating BRAF mutants have been identified in variety of cancers where constitutive activation of the MEK/ERK MAPK signaling pathway is the key for tumorigenesis, and they have been shown to be client proteins for HSP90. Accordingly, HSP90 inhibition can suppress certain cancer-causing client proteins and therefore represents an important therapeutic target. The molecular mechanism underlying the anti-cancer effect of HSP90 inhibition is complicated. Geldanamycin and its derivatives have been shown to induce the depletion of mutationally-activated BRAF through several mechanisms. In this review, we will describe the HSP90-inhibitory mechanism, focusing on recent progress in understanding HSP90 chaperone structure-function relationships, the identification of new HSP90 client proteins and the development of HSP90 inhibitors for clinical applications.

Fukuyo Y ，Hunt CR ，Horikoshi N 《-》

Geldanamycin-induced PCNA degradation in isolated Hsp90 complex from cancer cells.

Wang X ，Heuvelman DM ，Carroll JA ，Dufield DR ，Masferrer JL ... -  《-》

Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors.

Powers MV ，Workman P 《ENDOCRINE-RELATED CANCER》

Hsp90 inhibition transiently activates Src kinase and promotes Src-dependent Akt and Erk activation.

Koga F ，Xu W ，Karpova TS ，McNally JG ，Baron R ，Neckers L ... -  《-》

Comparison of 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 and client proteins in melanoma models.

Smith V ，Sausville EA ，Camalier RF ，Fiebig HH ，Burger AM ... -  《CANCER CHEMOTHERAPY AND PHARMACOLOGY》