| NVP-AUY922 is a potent and selective heat shock protein 90 (HSP90) inhibitor with Kd of 1.7 nM. NVP-AUY922 inhibits HSP90α and HSP90β with IC50 of 13 and 21 nM, respectively. The IC50 for NVP-AUY922 against the HSP90 family members GRP94 and TRAP-1 are 535 and 85 nM, respectively. In vitro, NVP-AUY922 potently inhibits proliferation of multiple human tumor cell lines (NQO1 polymorphism and isogenic BE2 cells). NVP-AUY922 also shows high uptake in HCT116 human colon carcinoma cell lines. NVP-AUY922 depletes HSP90 client proteins in a concentration- and time-dependent manner. NVP-AUY922 inhibits tumor cell chemomigration, invasion, and haptotaxis. NVP-AUY922 also inhibits endothelial cell functions related to angiogenesis. [1] NVP-AUY922 inhibits six breast cancer cell lines (BT-474, BT20, MDA-MB-231, MDA-MB-468, SkBr3, and MCF-7) tested with GI50 values of 3.1, 4.0, 7.0, 6.3, 3.3 and 8.8 nM. NVP-AUY922 is highly effective at inhibiting the growth of five human breast cancer explants (MAXF 1162, MAXF 1322, MAXF 1384 and MAXF 401) tested, with GI50 values of 304, 29, 209 and 78 nM, respectively. In BT-474 cells, NVP-AUY922 causes a concentration -dependent decrease in the amount of HSP90α co-immunoprecipitating with p23. Treatment of BT-474 cells with 50 nM NVP-AUY922 causes a clear dissociation between p23 and HSP90α, resulting in the loss of HSP90α from p23 immunoprecipitates. [2] Treatment of the A2780 cells with 50 nM NVP-AUY922 for 24 hours results in a 43.2% reduction of VEGF levels in the culture medium, compared with the culture medium of nontreated cells. [3] NVP-AUY922 potently radiosensitizes cells in vitro at low nanomolar concentrations with a concurrent depletion of radioresistance-linked client proteins. NVP-AUY922 ubiquitously inhibits resolution of dsDNA damage repair correlating to delayed Rad51 foci formation in all cell lines tested. Additionally, NVP-AUY922 induces a stalled mitotic phenotype, in a cell line-dependent manner, in HeLa and HN5 cell lines irrespective of radiation exposure. NVP-AUY922 also induces aberrant mitotic entry in all cell lines tested in the presence of radiation-induced DNA damage. [4] NVP-AUY922 inhibits NCI-N87 cells, SNU-216 cells and BEAS-2B cells with IC50 of 3.48, 11.99 and 28.49 nM, respectively. NVP-AUY922 potently induces the degradation of growth factor receptors and other client proteins including HER-2, Akt and thymidylate synthase. [5] In vivo, NVP-AUY922 inhibits HSP90 and exhibits potent antitumor efficacy in human tumor xenografts. [1] NVP-AUY922 exhibits potent antitumor activity at well-tolerated dose levels against an ERBB2-overexpressing estrogen receptor (ER)-positive breast cancer xenograft. [2] NVP-AUY922 treatment decreases mean vessel density (MVD) and Ki67 staining in responding A2780 tumors. [3] Radiosensitization by NVP-AUY922 is verified in vivo in a human head and neck squamous cell carcinoma xenograft model in athymic mice. [4] |
