Hsp90 as a Target for Drug Development

Statistical Model to Analyze Quantitative Proteomics Data Obtained by 18O/16O Labeling and Linear Ion Trap Mass Spectrometry

“…Some of these proteins have been directly or indirectly associated with angiogenesis in endothelial cells. In addition to Hsp70, a chaperone reported to display down-regulation in HUVECs exposed to VEGF (36, 37), we also found a down-regulation of Hsp90, and some studies show that inhibitors of this protein have antiangiogenic activity in vivo (58,59). Down-regulation of adipose triglyceride lipase is also consistent with a proangiogenic event because this protein acts as a receptor for pigment epithelium-derived factor (57), a strong endogenous inhibitor of angiogenesis (71).…”

HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways

“…When a client protein binds to HSP90 or when HSP90 is inhibited, HSF1 is activated and released from the co-chaperone complex. Activated HSF1 translocates to the nucleus where it initiates the transcription of heat shock responding proteins including heat shock protein 70 (HSP70) [53]. Increased HSP70 and translocation of HSF1 are often used as indicators for the inhibition of HSP90 [34,35].…”

Drug-Mediated Targeted Disruption of Multiple Protein Activities Through Functional Inhibition of the Hsp90 Chaperone Complex

“…The stable part of the clamp is configured by the constitutively interacting dimerization domains located at the COOH-terminus of Hsp90 (Fig. (2)) [2,8,13,14,16,[24][25][26][27][28][29][30]. The extensive conformational alterations during the course of ATPase cycle are unambiguously related to Hsp90 chaperone activities, but conflicting theories have been proposed as to the nature of specific and individualized functions these might be.…”

“…(4)) and (Table 1). While substrates, also referred to as client proteins, typically rely on Hsp90 chaperone functions for proper folding, stability and specific activities, cochaperones support Hsp90 to selectively bind and handle target clients [2,6,9,17,28]. A subset of co-chaperones contains the socalled tetratricopeptide repeats (TPRs: degenerate 34 amino acid residue motifs), which can specifically interact with the very carboxyl-terminal pentapeptide sequence of Hsp90, MEEVD (Fig.…”

“…This novel small-molecule inhibitor exhibited similar cellular properties to 17-AAG, thus displaying the potential for clinical use in the near future. An even more promising pyrazole derivative (VER50589) has been recently reported to show high inhibitory potency against Hsp90 chaperone function at extremely low nanomolar levels (K d 5 nM), as well as in vivo anti-tumor activity in an animal model [28,30,50,63,109,112].…”