Geldanamycin and its anti-cancer activities

Yayoi Fukuyo, Clayton R. Hunt, Nobuo Horikoshi

Research output: Contribution to journalReview articlepeer-review

140 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)24-35
Number of pages12
JournalCancer Letters
Issue number1
StatePublished - Apr 1 2010


  • 17-AAG/DMAG
  • BRAF(V600E)
  • Client protein
  • Geldanamycin
  • HSP90
  • MAPK signaling pathway
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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