Protein homeostasis (proteostasis) is inextricably tied to cellular health and organismal lifespan. PN through targeting molecular chaperones and assess the potential of the chemical biology of proteostasis. use; examples include epigallocatechin gallate [81] (inhibits several non-chaperone targets [82-86]) cisplatin [87] (damages DNA [88]) and silybin [89] (inhibits P-glycoprotein [90] and cytochrome P450 [91]). A particularly interesting class of small-molecules is capable of modulating co-chaperone access to the EEVD-motif in the HSP90 C-terminus. The macrocyclic peptide “compound 2” [92] (Fig. 3) was discovered in a structure-activity-relationship study on the Sansalvamide A pharmacophore and was shown to allosterically prevent binding of HSP90 co-chaperones IP6K2 FKBP38 FKBP52 and HOP in a biochemical Ciclopirox assay using purified proteins [93]. In a separate study a high-throughput screen that used an assay to monitor the HSP90-TPR2A protein-protein interaction revealed a small-molecule C9 which has a 7-azapteridine core that directly binds several TPR-containing co-chaperones [94 95 C9 directly binds the TPR2A domain of HOP as assessed by fluorescence-polarization and isothermal titration calorimetry presumably via the peptide groove where the co-chaperone-chaperone protein-protein interaction occurs. The feasibility of targeting HSP90 co-chaperones is further supported by the discovery that the tetranortriterpenoid natural product gedunin [96] mediates apoptotic cancer cell death through binding p23 [97]. Application of small-molecule HSP90 Ciclopirox modulators Since the early observation that geldanamycin has cytotoxic activity in cancer cell lines significant effort has been expended to develop HSP90 inhibitors for the treatment of cancer [51] but these efforts have yielded limited success. Despite many clinical trials there is still not a single FDA-approved HSP90 inhibitor which is largely due to the toxicity of candidate compounds. Although the early clinical trials may sustain the initial concerns raised with Ciclopirox respect to pharmacological modulation of chaperones many of the clinical candidates exhibit only modest selectivity among HSP90 isoforms [98] and perhaps modulators with greater isoform fidelity may prove less toxic. Additionally because HSP90 family members are expressed in each subcellular compartment it could be argued that increased regulatory control may come from the development of isoform-selective inhibitors. The development of isoform-selective HSP90 inhibitors is challenging because of the Ciclopirox high degree of structural similarity among the four human paralogues however recent reports suggest progress on paralogue-specific inhibitors [99 100 Some of these paralogue-specific inhibitors exhibit different phenotypic outcomes relative to their non-selective counterparts for example that GRP94 is disproportionately involved in the chaperoning of the HER2 protein in SKBr3 breast cancer cell lines relative to the other HSP90 isoforms [101]. Likewise inhibitors optimized for HSP90 α/β specificity displayed lower toxicity than pan-inhibitors when characterized in a cell-based model that monitored mutant Huntingtin clearance [102]. While conceptually promising the treatment of neurodegenerative diseases using HSP90 inhibitors has been complicated by activation of the heat shock response and the fact that inhibition of HSP90 disfavors association and stabilization of the oligomerization-prone clients which in-turn promotes degradation [103]. This highlights an important consideration of HSP90 inhibitors that general inhibition of HSP90 client interaction will have both positive and negative effects on cell protective mechanisms because of its central role in many cellular processes. Development of HSP90 inhibitors Goat polyclonal to IgG (H+L)(PE). with differential effects on clients however could have selective effects on diseased tissues. Altogether the application of HSP90 inhibitors toward modification of the PN in cancer has hinted that a highly conserved chaperone system may be targeted in living cells but this must be carefully controlled. Preliminary indications suggest that small-molecule HSP90 modulators could have broad benefits in disease. Targeting the ATP-binding site has successfully afforded many potent HSP90 inhibitors but selectivity is usually only modest in large part due to high structural similarity in this.