TY - JOUR
T1 - Rational design of shepherdin, a novel anticancer agent
AU - Plescia, Janet
AU - Salz, Whitney
AU - Xia, Fang
AU - Pennati, Marzia
AU - Zaffaroni, Nadia
AU - Daidone, Maria Grazia
AU - Meli, Massimiliano
AU - Dohi, Takehiko
AU - Fortugno, Paola
AU - Nefedova, Yulia
AU - Gabrilovich, Dmitry I.
AU - Colombo, Giorgio
AU - Altieri, Dario C.
N1 - Funding Information:
We thank B. Vogelstein for HCT116 cells, M. Bally for MDA-MB-435 cells, T.S. Edgington for discussion, D.S. Garlick for veterinary pathology, and C. Shiffer and C.R. Matthews for reading the manuscript. We also thank J. Crawford and J. Elliott at the W.M. Keck Biotechnology Research Center at Yale University School of Medicine for peptide and peptidomimetic synthesis and characterization. This work was supported by NIH grants HL54131, CA78810, and CA90917, and by grants provided by AIRC (Italian Association for Cancer Research) and the Italian Ministry of Health (grants RF02/171 and RF02/184). M.P. is supported by a fellowship from FIRC.
PY - 2005/5
Y1 - 2005/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ccr.2005.03.035
DO - 10.1016/j.ccr.2005.03.035
M3 - Article
C2 - 15894266
AN - SCOPUS:21144437911
SN - 1535-6108
VL - 7
SP - 457
EP - 468
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -
