Current Cancer Drug Targets - Volume 3, Issue 5, 2003

In this issue of Current Cancer Drug Targets we are featuring a series of articles on the subject of Hsp90 Molecular Chaperone Inhibitors: Opportunities and Challenges. This is an exciting and timely topic. As tends to be the case these days in the best translational science, the biology of a hot area is still breaking at the same time as the first attempts at therapeutic exploitation are underway. This has advantages and disa Read More

The Hsp90 molecular chaperone has emerged as one of the most exciting targets for cancer drug development. Hsp90 is overexpressed in many malignancies, very likely as a result of the stress that is induced both by the hostile cancer microenvironment and also by the mutation and abberant expression of oncoproteins. A particularly attractive feature of Hsp90 as a cancer drug target is that it is required for the conf Read More

Understanding the mode of action of Hsp90 requires that molecular detail of its interactions with client proteins and co-chaperones are known. The structure determination of the N-terminal domain of Hsp90 / Hsp90β, proof that it is an ATPase, that this activity is regulated and the identification of cochaperones that facilitate Hsp90 function were landmarks towards understanding conformational changes in Hsp90 brought about Read More

The currently used Hsp90 inhibitors, geldanamycin, herbimycin A and radicicol, were isolated many years ago from Streptomyces and fungi originally for their antiprotozoal activity, herbicidal activity and antifungal activity, respectively. In the mid 1980s, it was found that the benzoquinone ansamycin antibiotics (herbimycin A, geldanamycin, and macbecin) reversed v-Src transformed cells to normal phenotyp Read More

HSP90 inhibitors such as 17AAG have the major therapeutic advantage that they exert downstream inhibitory effects on multiple oncogenic client proteins. They therefore block several mission critical cancercausing pathways and have the potential to modulate all of the hallmark biological features of malignancy. Consistent with this combinatorial anti-oncogenic profile, 17AAG exhibits broad-spectrum antitumour activity ag Read More

The molecular chaperone heat shock protein 90 (Hsp90) is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and / or survival. It is also critical for the function of many normally expressed proteins, including protein kinases, steroid receptors and other transcription factors, and it may protect the cell from incapacitating or deleterious mutation Read More

In their role as molecular chaperones, heat shock proteins serve as central integrators of protein homeostasis within cells. As part of this function, they guide the folding, assembly, intracellular disposition and proteolytic turnover of many key regulators of cell growth, differentiation and survival. Not surprisingly then, heat shock proteins are over expressed in many types of cancer, and induction of the stress response may actuall Read More

Radicicol, a macrocyclic antibiotic produced by fungi, was originally isolated many years ago, and was described as tyrosine kinase inhibitor. We also rediscovered radicicol as an inhibitor of signal transduction of oncogene products, such as K-ras and v-Src, using yeast and mammalian cell-based assays. In a study of mechanisms of action, it was revealed that radicicol depletes the Hsp90 client signaling molecules in cells, an Read More

The Hsp90 chaperones play a key role in regulating the physiology of cells exposed to environmental stress and in maintaining the malignant phenotype in tumor cells. Agents that interfere with the function of the chaperone may thus be beneficial in the treatment of cancers. The ansamycins (geldanamycin and herbimycin) and the unrelated natural product radicicol were found to bind to the N-terminal pocket of Read More

17-allylamino, 17-demethoxygeldanamycin (17AAG; NSC 330507) is the first modulator of heat shock protein 90 (Hsp90) to enter clinical trials. Hsp90 serves a chaperone role to properly fold and deliver client proteins to appropriate intracellular locations. Interest in Hsp90 modulators for the experimental therapeutics of cancer has arisen based on pre-clinical evaluations suggesting that Hsp90 client proteins regulate sign Read More

The potential clinical applications of the prototype first-in-class Hsp90 inhibitor 17AAG and other emerging Hsp90 drugs are very exciting. Rigorously planned and executed clinical trials, incorporating measurement of appropriate biomarkers and pharmocodynamic endpoints are critical for selecting the optimal dose and schedule. A detailed understanding of the molecular mode of action of Hsp90 inhibitors alongside the Read More