Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy

Abstract

In this review recent progress in the development of heat shock proteins (Hsp90) in oncogenesis is illuminated. Particular emphasis is put on inhibitors such as geldanamycin and analogues that serve as a natural product show case. Hsp90 has emerged as an important target in cancer therapy and/or against pathogenic cells which elicit abnormal Hsp patterns. Competition for ATP by geldanamycin and related compounds abrogate the chaperone function of Hsp90. In this context, this account pursues three topics in detail: a) Hsp90 and its biochemistry, b) Hsp90 and its role in oncogenesis and c) strategies to create compound libraries of structurally complex inhibitors like geldanamycin on which SAR studies and the development of drugs that are currently in different stages of clinical testing rely.

Quality Control of a Cytoplasmic Protein Complex

“…4E). Neither deletion of STI1 nor the inhibition of Hsp90 chaperones by geldanamycin (44,45) showed any effect on the elimination of orphan Fas2 (data not shown).…”

“…chaperones (SSA2, SSA3, and SSA4) and carrying a temperature-sensitive allele of the fourth Hsp70 gene, SSA1 (allele ssa1- 45), carrying a mutation in the peptide-binding domain (40). As control, a strain deleted in SSA2, SSA3, and SSA4 but carrying wild type SSA1 was used.…”

Thermodynamic Analysis of the Geldanamycin–Hsp90 Interaction in a Whole Cell Lysate Using a Mass Spectrometry-Based Proteomics Approach

“…Geldanamycin, which binds to the N-terminal ATP-binding domain of Hsp90, inhibits the ATPase activity of Hsp90 and prevents binding of a co-chaperone, p23/Sba1, to Hsp90 [14][15][16][17]. The effects of geldanamycin and a number of geldanamycin derivatives against cancer and disease states have been well-studied over the years [9,13,18,19]. One measurement that has been elusive in these studies is the binding affinity of geldanamycin to Hsp90.…”

“…Geldanamycin ( Figure 1) is one of several natural product Hsp90 inhibitors that exhibit anti-cancer activity by disrupting the association of Hsp90 with client proteins [12,13]. Geldanamycin, which binds to the N-terminal ATP-binding domain of Hsp90, inhibits the ATPase activity of Hsp90 and prevents binding of a co-chaperone, p23/Sba1, to Hsp90 [14][15][16][17].…”

Are Heat Shock Proteins Druggable Candidates?

“…The cancer cells were only challenged when both the constitutive and inducible forms of the proteins were down-regulated (Schlecht et al, 2013). In addition, inhibition of Hsp90 has been shown to induce Hsp70 and Hsp27 (reviewed by Franke et al, 2013). Therefore targeting the functional association of Hsp70 and Hsp90 might be a more effective intervention than inhibiting each of the two molecular chaperones.…”