HSP990 (NVP-HSP990) is a potent and selective inhibitor of HSP90 with IC50 values of 0.6, 0.8 and 8.5 nM for Hsp90α, Hsp90β and Grp94, respectively [1].
Heat shock protein 90 (HSP90) is a chaperone protein that stabilizes proteins against heat stress, assists proteins to fold properly and aids in protein degradation. Also, HSP90 stabilizes proteins required for tumor growth.
HSP990 (NVP-HSP990) is a potent and selective HSP90 inhibitor. NVP-HSP990 bound to the N-terminal ATP-binding domain of Hsp90. NVP-HSP990 inhibited TRAP1 ATPase activity by 90% with IC50 value of 320 nM. In GTL-16 cells, NVP-HSP990 destabilized the Hsp90-p23 complex in a concentration- and time-dependent way. Also, NVP-HSP990 decreased c-Met with EC50 value of 37 nM and induced Hsp70 with EC50 value of 20 nM. NVP-HSP990 inhibited ERK and AKT phosphorylation with EC50 values of 11 and 6 nM respectively and thus inhibited ERK and AKT activation. In five human tumor cell lines, NVP-HSP990 inhibited cell growth with GI50 values of 4-40 nM [1]. In glioma tumor-initiating cells, NVP-HSP990 inhibited cell growth with IC50 value of 10-500 nM in a dose-dependent way and reduced CDK2 and CDK4, thus disrupting cell-cycle control [2].
In the GTL-16 gastric cancer mice model, NVP-HSP990 exhibited antitumor efficacy [1].
References:
[1]. Menezes DL, Taverna P, Jensen MR, et al. The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo. Mol Cancer Ther, 2012, 11(3): 730-739.
[2]. Fu J, Koul D, Yao J, et al. Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells. Cancer Res, 2013, 73(10): 3062-3074.
