HSP990 (NVP-HSP990)Hsp90 inhibitor, potent and selective CAS# 934343-74-5 |
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Quality Control & MSDS
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| Cas No. | 934343-74-5 | SDF | Download SDF |
| PubChem ID | 46216556 | Appearance | Powder |
| Formula | C20H18FN5O2 | M.Wt | 379.39 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | HSP-990 | ||
| Solubility | DMSO : ≥ 33 mg/mL (86.98 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | (7R)-2-amino-7-[4-fluoro-2-(6-methoxypyridin-2-yl)phenyl]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one | ||
| SMILES | CC1=NC(=NC2=C1C(=O)NC(C2)C3=C(C=C(C=C3)F)C4=NC(=CC=C4)OC)N | ||
| Standard InChIKey | WSMQUUGTQYPVPD-OAHLLOKOSA-N | ||
| Standard InChI | InChI=1S/C20H18FN5O2/c1-10-18-16(26-20(22)23-10)9-15(25-19(18)27)12-7-6-11(21)8-13(12)14-4-3-5-17(24-14)28-2/h3-8,15H,9H2,1-2H3,(H,25,27)(H2,22,23,26)/t15-/m1/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | NVP-HSP990 is a potent and selective Hsp90 inhibitor, with IC50 values of 0.6, 0.8, and 8.5 nM for Hsp90α, Hsp90β, and Grp94, respectively.In Vitro:NVP-HSP990 is a potent and selective Hsp90 inhibitor, with IC50 values of 0.6, 0.8, and 8.5 nM for Hsp90α, Hsp90β, and Grp94, respectively. NVP-HSP990 (10 μM) shows no affect the ATPase activity of topoisomerase II, a GHKL (Gyrase, Hsp90, Histidine Kinase, MutL) family ATPase, closely related to Hsp90. NVP-HSP990 also exerts efficient effects on c-Met, Hsp70, p-ERK and p-AKT in CTL-16 cells, with EC50s of 37 ± 4, 20 ± 2, 11 ± 1, and 6 ± 1 nM, respectively. NVP-HSP990 suppresses the proliferation of BT474, A549, H1975 and MV4;11 cells, with GI50s of 7 ± 2, 28 ± 5, 35 ± 4, and 4 ± 1 nM, respectively[1]. NVP-HSP990 inhibits cellular proliferation of GTL-16, with an EC50 of 14 nM[2]. NVP-HSP990 (5-500 nM) inhibits the multiple myeloma cell lines, with IC50s of 27-49 nM after treatment for 72 h. NVP-HSP990 induces apoptosis in multiple myeloma cell lines (0-100 nM), leads to cell cycle arrest in the G2/M phase (25-200 nM), and induces apoptosis via caspase-8 followed by caspase-3 activation (100 nM). NVP-HSP990 increases HSP70 expression and interacts with Akt and ERK signaling. Moreover, NVP-HSP990 (100 nM) in combination with melphalan, causes synergistic effects on growth inhibition in multiple myeloma cells and increases cleavage of caspase-3, caspase-8, and caspase-9 and activates caspase-2[3].In Vivo:NVP-HSP990 (2.5 to 5 mg/kg twice weekly, or 5 to 15 mg/kg weekly, p.o.) causes dose proportional antitumor efficacy, without obvious loss or overt signs of toxicity in a GTL-16 tumor bearing mice. NVP-HSP990 (5 or 10 mg/kg weekly, p.o.) also results in significant inhibition of tumor growth in BT-474 breast cancer model. NVP-HSP990 (5 mg/kg twice weekly or 15 mg/kg weekly, p.o.) inhibits the growth of tumor in the MV4;11 xenograft model. Furthermore, NVP-HSP990 (0.5 mg/kg every day, 14, 5 mg/kg twice weekly, or 15 mg/kg weekly, p.o.) displays antitumor efficacy in H1975 and A549 tumor models[1]. NVP-HSP990 (5, 15 mg/kg, p.o.) shows prolonged suppression of c-Met levels with 30% and 50% reduction and exhibits antitumor activities in GTL-16 tumor xenograft[2]. References: | |||||
HSP990 (NVP-HSP990) Dilution Calculator
HSP990 (NVP-HSP990) Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.6358 mL | 13.1791 mL | 26.3581 mL | 52.7162 mL | 65.8953 mL |
| 5 mM | 0.5272 mL | 2.6358 mL | 5.2716 mL | 10.5432 mL | 13.1791 mL |
| 10 mM | 0.2636 mL | 1.3179 mL | 2.6358 mL | 5.2716 mL | 6.5895 mL |
| 50 mM | 0.0527 mL | 0.2636 mL | 0.5272 mL | 1.0543 mL | 1.3179 mL |
| 100 mM | 0.0264 mL | 0.1318 mL | 0.2636 mL | 0.5272 mL | 0.659 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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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.
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Increased radiosensitivity and radiothermosensitivity of human pancreatic MIA PaCa-2 and U251 glioblastoma cell lines treated with the novel Hsp90 inhibitor NVP-HSP990.[Pubmed:23448094]
Radiat Oncol. 2013 Feb 28;8:42.
BACKGROUND AND PURPOSE: Heat shock Protein 90 (Hsp90) is a molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins involved in oncogenic signaling and in the regulation of radiosensitivity. It is upregulated in response to stress such a heat. Hyperthermia is a potent radiosensitizer, but induction of Hsp90 may potentially limit its efficacy. Our aim was to investigate whether the new Hsp90 inhibitor NVP-HSP990 increases radiosensitivity, thermosensitivity and radiothermosensitivity of human tumor cell lines. MATERIAL AND METHODS: U251 glioblastoma and MIA PaCa-2 pancreatic carcinoma cells were used. To determine clonogenic survival, colony forming assays were performed. Cell viability and proliferation were assesed by Trypan blue staining. Cell cycle and apoptosis analyses were performed by flow cytometry. DAPI staining was used to detect mitotic catastrophe. RESULTS: NVP-HSP990 increased the thermosensitivity, radiosensitivity and radio-thermosensitivity of both cell lines in clonogenic assays. 72 hours after irradiation with 4 Gy, a significant reduction in cell number associated with considerable G2/M acumulation and mitotic catastrophe as well as cell death by apoptosis/necrosis was observed. CONCLUSIONS: Treatment with NVP-HSP990 strongly sensitized U251 and MIA PaCa-2 cells to hyperthermia and ionizing radiation or combination thereof through augmentation of G2/M arrest, mitotic catastrophe and associated apoptosis.
Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells.[Pubmed:23492364]
Cancer Res. 2013 May 15;73(10):3062-74.
Genetic heterogeneity and signaling alterations diminish the effectiveness of single-agent therapies in glioblastoma multiforme (GBM). HSP90 is a molecular chaperone for several signaling proteins that are deregulated in glioma cells. Thus, HSP90 inhibition may offer an approach to coordinately correct multiple signaling pathways as a strategy for GBM therapy. In this study, we evaluated the effects of a novel HSP90 inhibitor, NVP-HSP990, in glioma tumor-initiating cell (GIC) populations, which are strongly implicated in the root pathobiology of GBM. In GIC cultures, NVP-HSP990 elicited a dose-dependent growth inhibition with IC50 values in the low nanomolar range. Two GIC subgroups with different responses were observed with an Olig2-expressing subset relatively more sensitive to treatment. We also showed that Olig2 is a functional marker associated with cell proliferation and response to NVP-HSP990, as NVP-HSP990 attenuated cell proliferation in Olig2-high GIC lines. In addition, NVP-HSP990 disrupted cell-cycle control mechanism by decreasing CDK2 and CDK4 and elevating apoptosis-related molecules. Mechanistic investigations revealed molecular interactions between CDK2/CDK4 and Olig2. Inhibition of CDK2/CDK4 activity disrupted Olig2-CDK2/CDK4 interactions and attenuated Olig2 protein stability. In vivo evaluation showed a relative prolongation of median survival in an intracranial model of GIC growth. Our results suggest that GBM characterized by high-expressing Olig2 GIC may exhibit greater sensitivity to NVP-HSP990 treatment, establishing a foundation for further investigation of the role of HSP90 signaling in GBM.
Design, structure-activity relationship, and in vivo characterization of the development candidate NVP-HSP990.[Pubmed:25368984]
J Med Chem. 2014 Nov 13;57(21):9124-9.
Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate.
