Current Topics in Medicinal Chemistry - Volume 9, Issue 15, 2009

Through the transcriptional/translational process, linear DNA is transformed into biologically active, three-dimensional proteins that provide the machinery necessary for cellular life. Elucidation of the processes involved in replicating and transcribing DNA led to some of the most important scientific discoveries during the 20th Century, however, the conformational maturation of linear information into tertiary and quaternary Read More

The molecular chaperone, heat shock protein 70 (Hsp70), acts at multiple steps in a protein's life cycle, including during the processes of folding, trafficking, remodeling and degradation. To accomplish these various tasks, the activity of Hsp70 is shaped by a host of co-chaperones, which bind to the core chaperone and influence its functions. Genetic studies have strongly linked Hsp70 and its co-chaperones to numerous diseas Read More

Hsp90 is involved in the maturation and activation of client proteins. Often these are key proteins involved in signal transduction and regulatory pathways that in a mutated and/or deregulated form sustain an oncogenic cellular state. Consequently, the malignancy is maintained with the aid of Hsp90 upon which the mutated proteins have become particularly dependent for their activity. The requirement for the Hsp90 chaper Read More

The molecular chaperone Hsp90 (90 kDa heat-shock protein) mediates many fundamental cellular pathways involved in cell proliferation, cell survival, and cellular stress response. Hsp90 is responsible for the correct conformational development, stability and function in crowded cell environments. Structural and computational biology studies have recently provided important insights into underlying molecular mecha Read More

The ansamycin class of natural products is well known for its anti-tumor effects and has been extensively studied by cancer researchers for nearly four decades. The first description of geldanamycin in the scientific literature appeared in 1970 and nearly thirty years later the semi-synthetic derivative 17-AAG, or tanespimycin, entered Phase 1 clinical trials. In the subsequent years, three additional geldanamycin derivatives h Read More

Heat shock protein 90 (Hsp90) is an ATP-dependent chaperone which is involved in the post-translational maturation and stabilization of over one hundred proteins (“its clients”). In the absence of Hsp90's chaperoning, its clients are misfolded and degraded via ubiquitin-proteasome pathway. HSP90 has become the focus of intense drug discovery efforts as its activity has been implicated in diverse pathologies ranging from on Read More

Hsp90 is a molecular chaperone with important roles in regulating the function of several proteins with potential pathogenic activity. Because many of these proteins are involved in cancer and neurodegenerative promoting pathways, Hsp90 has emerged as an attractive therapeutic target in these diseases. Molecules that bind to the N-terminal nucleotide pocket of Hsp90 inhibit its activity, and consequently, disrupt client prot Read More

The 90 kDa heat shock protein (Hsp90) has become a validated target for the development of anti-cancer agents. Several Hsp90 inhibitors are currently under clinical trial investigation for the treatment of cancer. All of these agents inhibit Hsp90's protein folding activity by binding to the N-terminal ATP binding site of the Hsp90 molecular chaperone. Administration of these investigational drugs elicits induction of the heat sh Read More

The Hsp90-dependence of many oncogenic proteins has precipitated a great deal of interest in Hsp90 as a drug target, as evidence mounts that Hsp90 inhibitors may be effective chemotherapeutic agents for the treatment of cancer. In addition, Hsp90-inhibitors have shown promise for the treatment of neurodegenerative diseases characterized by the accumulation of toxic denatured protein aggregates. The development o Read More

Twenty-five years ago the first small molecule inhibitors of Hsp90 were identified. In the intervening years there has been dramatic progress in basic scientific understanding of the Hsp90 chaperone machinery and in the role of Hsp90 in malignancy. The first-in-class Hsp90 inhibitor 17-AAG entered into Phase I clinical trials in 1999. There are now 13 Hsp90 inhibitors in clinical trial, representing multiple drug classes, and hun Read More