At 10 uM there is no inhibition of human HSP72 ATPase or decatenation activity of human topoisomerase II and little or no activity against a range of 13 kinases. In a screen of 14 additional enzymes and 67 receptors, NVP-AUY922 exhibited >50% inhibitory activity at 10 uM against only 6 receptors and 1 enzyme; further profiling showed NVP-AUY922 to be >50-fold selective for HSP90.
In cell validation
Potency in cells:
GI50*
from 2.3 to 39 nM in various tumour cells, (*Growth Inhibition 50%)
Potency assay (cells):
Extensive evidence is available to validate depletion of client proteins (eg kinases CDK4, RAF and ERBB2/HER2 and transcription factors such as the estrogen and androgen receptor) together with increased expression of HSF1-regulated genes such as HSP72 and HSP27 as on-target molecular effects of HSP90 inhibitors) Eccles et al. 2008 (DOI: 10.1158/0008-5472.CAN-07-5256) and Banerji et al. 2005 (DOI: 10.1158/1078-0432.CCR-05-0518)
Toxicity
Cytoxicity assay:
No
In vivo validation
Organism:
Mouse
Dose:
50 mg/Kg
Route of delivery:
IntravenousIntraperitoneal
Plasma half life:
15 h in Tumor2 h in Plasma
Systemic clearance:
0.143 L/h in Plasma 0.020 L/h in Tumor
Cmax:
49 uM in Plasma14 uM in Tumor
Tmax:
0.25 h
Target engagement assay:
Therapeutic activity was tested in established human xenografts (colon, glioblastoma, breast, ovarian, and prostate) providing evidence of antitumour activity.
Evidence of HSP90 inhibition comes from changes in the biomarkers as reported in Banerji et al 2005 (DOI: 10.1158/1078-0432.CCR-05-0518)