NVP-HSP990, as a novel oral Hsp90 inhibitor, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nanomolar IC(50) value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.
|Cell lines||GTL-16, BT-474, A549, NCI-H1975 and MV4;11 cell lines|
|Preparation method||Cell proliferation and apoptosis assays Cells were treated with NVP-HSP990 or 17-AAG for 72 hours, and cell viability was determined by CellTiter-Glo Luminescent Cell Viability assay from Promega. Soft agar clonogenic assays with primary human tumors were conducted at Oncotest GmbH|
|Incubation time||72 h|
|Animal models||Human tumor xenograft models GTL-16, NCI-H1975, BT474, and MV4;11|
|Formulation||100% polyethylene glycol (PEG400)|
|Dosages||a single dose of 15 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Source||Mol Cancer Ther (2012). Figure 1. NVP-HSP990|
|Cell Lines||GTL-16 cell line|
|Incubation Time||72 h|
|Results||NVP-HSP990 is based on a 2-amino-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one scaffold, which is structurally distinct from other known Hsp90 inhibitors. Acocrystal structure solved to 1.5A resolution (manuscript in preparation) shows that NVP-HSP990 binds to the Nterminal ATP-binding domain of Hsp90.|
The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo.
Menezes DL, et al. Mol Cancer Ther. 2012 Mar;11(3):730-9. PMID: 22246440.
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