Table 2.

Targeting the Hsp90-Cdc37-client protein interaction to disrupt Hsp90 chaperone machinery

The potential approaches to disrupt the Hsp90-Cdc37-client protein interaction	Related mechanisms	References
Targeting Cdc37
siRNAs or shRNA	Silencing Cdc37	[56, 57]
Targeting Cdc37-client interaction
4,5,6,7-Tetrabromobenzotriazole	CK2 inhibitors, suppressing Cdc37 phosphorylation at Ser13 site	[59]
PP5 mutation	Suppressing Cdc37 dephosphorylation	[48]
Vemurafenib	B-raf inhibitor. Antagonize Cdc37 interaction with kinases	[67]
Lapatinib	EGFR/HER2 inhibitor. Antagonize Cdc37 interaction with kinases	[67]
Targeting Hsp90-Cdc37 interaction
Celastrol	Blocking the critical interaction of Hsp90 at Glu33 and Cdc37 at Arg167	[68, 69]
Sulforaphane	Disrupting the formation of Hsp90-Cdc37 complex by direct modification of specific amino acids residues of Hsp90	[70]
FW-04-804	Binding sites at Gln133 and Glu47/Arg46 of Hsp90	[71, 72]
Withaferin A	Blocking several H-bond between Hsp90-Cdc37 interaction, like Ser113 (Hsp90)-Gln208 (Cdc37) bond and Gln133 (Hsp90)-Arg166 (Cdc37) bond	[73–75]
Kongensin A	Covalently binds to a cysteine 420 in the middle domain of Hsp90 and dissociates Hsp90 from Cdc37	[76, 77]
Platycodin D	H-bond connection with Hsp90 at Arg32 and Phe200 and Cdc37 at Asp169 and Asp170	[78, 79]
Pep-1	Cdc37-derived peptides, bound to Hsp90 N-terminal domain and inhibited Hsp90 ATPase activity	[80]

There are three potential approaches to disrupt the function of Hsp90 chaperone machinery: targeting Cdc37, Cdc37-client protein interaction, and Hsp90-Cdc37 interaction