Table 3.
Key data concerning orthosteric Hsp90 inhibitors Geldanamycin, Radicicol, and PU-H71.
| Inhibitor | Structure | Selected bioactivity indicatorsa | Contact residuesb | PDBc | Clinical trialsd | Other targetse |
|---|---|---|---|---|---|---|
| Geldana mycin |  |
IC50f = 15.8 nM (104) EC50g = 30 nM (105) Kdh = 1.35 μM (106) |
N51, S52, D54, A55, K58, D93, I96, M98, D102, N106, L107, K112, G135, V136, G137, F138, Y139 | 1YET (Hsp90) (107) | (None active or recruiting) | Nitric oxide synthase (104); oncogene product p185erbB−2 protein tyrosine-kinase (104, 108, 109); src protein tyrosine-kinase (110) |
| Radicicol |  |
IC50f = 37.5 nM (104) EC50i = 25 nM (111) Kdj = 2.2 nM (112), 3.04 nM (113) |
L48, N51, S52, D54, A55, K58, D93, I96, M98, N106, L107, F138, T184, V186 | 4EGK (Hsp90) (114) | (None active or recruiting) | Topoisomerase VI (115); Pyruvate dehydrogenase kinase (116); Carbonyl reductase 1 (117); |
| PU-H71 |  |
IC50f = 50 nM (118) EC50k = 16 nM (118) Kdh = 780 nM (106) |
N51, S52, A55, K58, D93, I96, G97, M98, L107, F138, Y139, V150, W162, T184 | 2FWZ (Hsp90) (119)4Z1F (Trap1) (120) |
Phase I: • metastatic breast cancer (with nab-paclitaxel) • safety and tolerability (with ruxolitinib) • advanced malignancies |
(None known) |
Chosen bioassays are limited to those that are directly comparable or similar in nature. Only human chaperones and cell lines have been considered. The list is merely indicative: a more complete list is available from the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/compound/5288382; https://pubchem.ncbi.nlm.nih.gov/compound/radicicol; https://pubchem.ncbi.nlm.nih.gov/compound/pu-h71 [accessed May 24, 2020]).
Residues with at least one atom detected to be closer than 3.0 Å to any atom in the ligand. Hydrogen atoms included in the analysis.
Human chaperone targets only.
Active and/or recruiting clinical trials only, as listed in the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/compound/5288382; https://pubchem.ncbi.nlm.nih.gov/compound/radicicol; https://pubchem.ncbi.nlm.nih.gov/compound/pu-h71 [accessed May 24, 2020]).
Documented, non-chaperone human targets only.
Antiproliferation/growth inhibition of SkBr3 breast cancer cell line.
Antiproliferative activity against HCT116 cells (luminescence assay).
Hsp90 competition with fluorescent geldanamycin (fluorescence assay).
Hsp90 binding (Western Blot on MCF-7 cell lysate).
Hsp90 binding (surface plasmon resonance analysis).
Hsp90 competition with fluorescent geldanamycin (fluorescence assay on SkBr3 cell lysate).