Blocking the protein folding machinery. Rational design of inhibitors of the molecular chaperone Hsp90 as new anticancer agents

摘要

Cancer therapy now aims at disabling oncogenic pathways that are selectively operative in tumor cells, so to spare normal tissues and limit side effects in humans. This "targeted therapy" relies on a better understanding of cancer genes, particularly those implicated in tumor cell proliferation and survival [1].. Accordingly, targeted inhibition of the Bcr-Abl kinase with small molecule antagonists has produced dramatic clinical responses in malignancies driven by this oncogene [2]. However, such approach may not be immediately available for the majority of tumors where multiple molecular abnormalities and genetic instabilities may elude the identification of one single, disease-driving oncogene [1]. Conversely, pathways that intersect multiple essential functions of tumor cells may provide wider therapeutic opportunities. A prime target for this strategy is Heat Shock Protein 90 (Hsp90), a molecular chaperone that oversees the correct conformations! development of polypeptides and protein refolding through sequential ATPase cycles and stepwise recruitment of cochaperones. This adaptive pathway contributes to the cellular stress response to environmental threats, including heat, heavy metal poisoning, hypoxia, etc.