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Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity.

Authors
  • Kasibhatla, Srinivas R
  • Hong, Kevin
  • Biamonte, Marco A
  • Busch, David J
  • Karjian, Patricia L
  • Sensintaffar, John L
  • Kamal, Adeela
  • Lough, Rachel E
  • Brekken, John
  • Lundgren, Karen
  • Grecko, Roy
  • Timony, Gregg A
  • Ran, Yingqing
  • Mansfield, Robert
  • Fritz, Lawrence C
  • Ulm, Edgar
  • Burrows, Francis J
  • Boehm, Marcus F
Type
Published Article
Journal
Journal of medicinal chemistry
Publication Date
Jun 14, 2007
Volume
50
Issue
12
Pages
2767–2778
Identifiers
PMID: 17488003
Source
Medline
License
Unknown

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin-2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 microM in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 microM in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (>80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17-desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.

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