Rational design of shepherdin, a novel anticancer agent.

Abstract

Anticancer agents that selectively kill tumor cells and spare normal tissues are urgently needed. Here, we engineered a cell-permeable peptidomimetic, shepherdin, modeled on the binding interface between the molecular chaperone Hsp90 and the antiapoptotic and mitotic regulator, survivin. Shepherdin makes extensive contacts with the ATP pocket of Hsp90, destabilizes its client proteins, and induces massive death of tumor cells by apoptotic and nonapoptotic mechanisms. Conversely, shepherdin does not reduce the viability of normal cells, and does not affect colony formation of purified hematopoietic progenitors. Systemic administration of shepherdin in vivo is well tolerated, and inhibits human tumor growth in mice without toxicity. Shepherdin could provide a potent and selective anticancer agent in humans.

• Authors: Janet Plescia, Whitney Salz, Fang Xia, Marzia Pennati, Nadia Zaffaroni, Maria Grazia Daidone, Massimiliano Meli, Takehiko Dohi, Paola Fortugno, Yulia Nefedova, Dmitry I Gabrilovich, Giorgio Colombo, Dario C Altieri
• Journal: Cancer cell (Cancer Cell) Vol. 7 Issue 5 Pg. 457-68 (May 2005) ISSN: 1535-6108 [Print] United States
• PMID: 15894266 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antennapedia Homeodomain Protein
• Antimetabolites, Antineoplastic
• BIRC5 protein, human
• Benzoquinones
• Enzyme Inhibitors
• Gene Products, tat
• HSP90 Heat-Shock Proteins
• Homeodomain Proteins
• Inhibitor of Apoptosis Proteins
• Lactams, Macrocyclic
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Nuclear Proteins
• Peptide Fragments
• Proto-Oncogene Proteins c-bcl-2
• Survivin
• Transcription Factors
• Tumor Suppressor Protein p53
• shepherdin
• Rifabutin
• tanespimycin
• Adenosine Triphosphate
• Cytochromes c
• Telomerase

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Antennapedia Homeodomain Protein
• Antimetabolites, Antineoplastic (chemistry, metabolism, pharmacology)
• Apoptosis (drug effects)
• Benzoquinones
• Binding Sites (genetics)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cytochromes c (metabolism)
• Drug Design
• Enzyme Inhibitors (pharmacology)
• Female
• Fibroblasts (drug effects)
• Gene Products, tat (genetics)
• HSP90 Heat-Shock Proteins (genetics, metabolism)
• HeLa Cells
• Homeodomain Proteins (genetics)
• Humans
• Inhibitor of Apoptosis Proteins
• Lactams, Macrocyclic
• Male
• Mice
• Mice, SCID
• Microtubule-Associated Proteins (metabolism)
• Models, Molecular
• Molecular Mimicry
• Neoplasm Proteins
• Nuclear Proteins (genetics)
• Peptide Fragments (chemistry, metabolism, pharmacology)
• Prostatic Neoplasms (drug therapy, pathology)
• Protein Binding (drug effects, genetics)
• Protein Conformation
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Rifabutin (analogs & derivatives, pharmacology)
• Stem Cells (drug effects)
• Survivin
• Telomerase (metabolism)
• Transcription Factors (genetics)
• Tumor Suppressor Protein p53 (genetics)
• Xenograft Model Antitumor Assays