Heat-shock protein 90 inhibitors as novel cancer chemotherapeutic agents

Abstract

Heat-shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and overexpressed signalling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2) and hypoxia inducible factor-1alpha (HIF-1alpha). Through specific interaction with a single molecular target, Hsp90 inhibitors cause the destabilisation and eventual degradation of Hsp90 client proteins, and they have shown promising antitumour activity in preclinical model systems. One Hsp90 inhibitor, 17-allylamino-geldanamycin (17-AAG), is currently in Phase I clinical trials. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signalling pathways on which cancer cells depend for growth and survival. Further, because of the unique effect that Hsp90 inhibition has on cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent.

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

“…These compounds bind into the ATP binding cleft of the N-terminal domain of Hsp90 preventing the chaperone from cycling between its ADP and ATP-bound conformations (Stebbins et al, 1997;Roe et al, 1999). Both natural products are highly active in preclinical models (Neckers and Neckers, 2002), but, owing to their poor solubility and other pharmacological issues, the clinical evaluation of geldanamycin and radicicol has not been pursued. In the case of geldanamycin, extensive medicinal chemistry efforts have been made to replace the 17-methoxy substituent and generate analogs with improved pharmaceutical properties.…”

Geldanamycin induces apoptosis in human gastric carcinomas by affecting multiple oncogenic kinases that have synergic effects with TNF-related apoptosis-inducing ligand

“…According to previous studies, the constitutive expression of Hsp90 was found to be 2-10 folds higher in malignant cells compared with normal cells (5). Additionally, several oncogenic proteins are dependent on Hsp90 to function, including B-RAF, protein kinase B (AKT) and extracellular signal-related kinase (ERK) (6). Inhibition of Hsp90 results in the dissociation of corresponding client proteins and induction of apoptosis in cancer cells, and may be accompanied by a reduction in chemotherapy resistance (7).…”

Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies

“…I n cancer cells, heat-shock protein 90 (Hsp90) interacts in a transformation-specific manner with kinases, hormone receptors, and transcription factors that are directly involved in driving multistep malignancy and also with mutated oncogenic proteins required for the transformed phenotype (1)(2)(3). Association of Hsp90 with client proteins is regulated both by the activity of its N-terminal ATPase domain, which binds and hydrolyses ATP to mediate a series of association-dissociation cycles between Hsp90 and client substrates, and by cochaperones, which modulate the formation of chaperone/client-specific complexes (4).…”