Rational design of shepherdin, a novel anticancer agent

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

Research output: Contribution to journalArticlepeer-review

261 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)457-468
Number of pages12
JournalCancer Cell
Volume7
Issue number5
DOIs
StatePublished - May 2005

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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