Rational design of shepherdin, a novel anticancer agent

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 ATIP 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.