Tanespimycin (17-AAG)

Compound status: 
Historic compound: While this compound has been used to interrogate specific protein targets, it is not a chemical probe and should not be used in assays that depend on a potent and selective modulator of the protein.
Note about activity: 

Tanespimycin, commonly referred as 17-AAG, is an HSP90 inhibitor related to the natural product geldanamycin which has the significant limitation that its potency in cells is highly dependent on the levels of the quinone reductase NQO1 (DT-diaphorase). Human cells with high levels of NQO1 are much more sensitive to tanespimicin/17-AAG than cells having low levels and those lacking activity due to NQO1 polymorphism. This effect is over and above the intrinsic sensitivity of HSP90 inhibition in cells and confounds the interpretation of the involvement of HSP90 in the cellular effects being studied, such as cell proliferation. The mechanism is that NQO1 converts the benzoquinone ansamycin tanespimicin/17-AAG to the hydroquinone form which is a more potent HSP90 inhibitor. The effect was first published by Kelland et al as long ago as 1999 using human cancer cell line panels and an isogenic cell line pair model. The dependence of 17-AAG sensitivity on NQO1 expression has subsequently been confirmed by other groups, most notably using very large human cancer cell line panels. Despite these findings and the discovery of other non-quinone containing HSP90 inhibitory chemotypes, tanespimycin/17-AAG continues to be used as a chemical probe for HSP90. If used at all, alternative chemotypes should also be used alongside tanespimycin/17-AAG, including the recommended resorcinol-class chemical probe luminespib and/or other HSP90 inhibitors such as the resorcinol onalespib and the purine class inhibitor BIIB021. Useful references: (Kelland et al 1999, Workman et al 2012, Guo et al 2006).

Probe Information