shepherdin and Breast-Neoplasms

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.

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