title: Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent.
abstract: BACKGROUND
  Despite an ever-improving understanding of the molecular biology of cancer, the treatment of most cancers has not changed dramatically in the past three decades and drugs that do not discriminate between tumor cells and normal tissues remain the mainstays of anticancer therapy. Since Hsp90 is typically involved in cell proliferation and survival, this is thought to play a key role in cancer, and Hsp90 has attracted considerable interest in recent years as a potential therapeutic target.
  
  
  METHODS
  We focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop.
  
  
  RESULTS
  It was demonstrated that this designed hybrid Antp-TPR peptide inhibited the interaction of Hsp90 with the TPR2A domain, inducing cell death of breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines in vitro. In contrast, Antp-TPR peptide did not affect the viability of normal cells. Moreover, analysis in vivo revealed that Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice.
  
  
  CONCLUSIONS
  These results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients.
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoecho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Horibe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kohno
authors.forename: Mari
authors.initials: M
authors.lastname: Haramoto
authors.forename: Koji
authors.initials: K
authors.lastname: Ohara
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D010446:Peptide Fragments / Q000737:chemistry; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C476884:HOPX protein, human; D018841:HSP90 Heat-Shock Proteins; D018398:Homeodomain Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C558008:hybrid Antp-TPR peptide