| CAS |
No.934343-74-5 |
| 英文名称 |
HSP990 |
| 分子式 |
C20H18FN5O2 |
| 分子量 |
379.39 |
| 溶解性 |
Soluble in DMSO(Need ultrasonic) |
| 纯度 |
≥98% |
| 外观(性状) |
Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| MDL |
MFCD22628859 |
| SMILES |
CC1=C2C(=NC(=N1)N)CC(NC2=O)C3=C(C=C(C=C3)F)C4=NC(=CC=C4)OC |
| InChIKey |
WSMQUUGTQYPVPD-OAHLLOKOSA-N |
| 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 |
| PubChem CID |
46216556 |
| 靶点 |
Hsp90 |
| 通路 |
Cell Cycle;Metabolic Enzyme&Protease |
| 背景说明 |
是一种有效的，选择性的 Hsp90 抑制剂。 |
| 生物活性 |
NVP-HSP990 is a potent， selective and orally active Hsp90 inhibitor， with IC50 values of 0.6， 0.8， and 8.5 nM for Hsp90α， Hsp90β， and Grp94， respectively.[1-3] |
| 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]. |
| 细胞实验 |
GTL-16 Cells (1 × 103) are plated into 96 well tissue culture plates and cultured at 37°C， 5% CO2. Serially diluted compounds (NVP-HSP990) are added to the cells and are incubated for 72 hrs. at 37°C， 5% CO2. Cell proliferation is determined using Cell Viability assay[2]. |
| 动物实验 |
Human tumor xenograft models GTL-16， NCI-H1975， BT474， and MV4;11 are implanted subcutaneously with 50% Matrigel in nude or severe combined immunodeficient mice. Mice are randomized into cohorts (10 mice/group for efficacy) when tumors reach 200 to 500 mm3. NVP-HSP990 is administered orally in a vehicle of 100% polyethylene glycol (PEG400). Tumor caliper measurements are converted into tumor volumes using the formula: [length × (width)2]/2. Relative tumor inhibition is calculated as %T/C = 100 × dT/dC， where， dT or dC = difference of mean tumor volume of drug treatment (T) or vehicle (C) on the final day of the study and the randomization volume. Statistical comparisons are conducted using a one-way ANOVA， followed by the Dunn or Tukey post hoc test. Differences are statistically significant at P [1]. |
| 激酶实验 |
His-tagged Hsp90α N-terminal domain protein (N-Hsp90α-His) is diluted to 2× the final concentration in the assay buffer consisting of 50 mM Hepes， pH 7， 6 mM MgCl2， 20 mM KCl and 0.1% BSA. The Hsp90 is dispensed into 96 well polypropylene plates at 50 μL per well. In a separate polypropylene plate， test compounds (NVP-HSP990) are diluted to 40× their final concentration in 100% DMSO. Serial dilutions in DMSO are made in 3-fold increments. 2.5 μL of diluted compounds are transferred to the 50 μL of Hsp90 and mixed. Background wells receive 25 μM (final concentration) radicicol. Biotin-radicicol is diluted into assay buffer at 2× the final concentration and 50 μL are added to the Hsp90/compound plate. DMSO is at a final concentration of 2.5%. Samples are incubated at room temperature for 2 hours before 50 μL are transferred to NeutrAvidin-coated plates. Plates are incubated 1 hour， washed 3× with DELFIA wash buffer (5 mM Tris， pH 7.5， 0.1% Tween 20， 0.1% sodium azide， 0.9% NaCl)， and then 50 μL per well of 3 nM Eu-anti-His diluted into DELFIA assay buffer are added. The plates are next incubated 2 hours at room temperature， washed 4×， and then 50 μL enhancement solution are added. Plates are gently shaken for 7-10 minutes before reading in a VICTOR2 instrument[2]. |
| 数据来源文献 |
[1]. Menezes DL， 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 Mar;11(3):730-9.
[2]. McBride CM， et al. Design， structure-activity relationship， and in vivo characterization of the development candidate NVP-HSP990. J Med Chem. 2014 Nov 13;57(21):9124-9.
[3]. Lamottke B， et al. The novel， orally bioavailable HSP90 inhibitor NVP-HSP990 induces cell cycle arrest and apoptosis in multiple myeloma cells and acts synergistically with melphalan by increased cleavage of caspases. Eur J Haematol. 2012 May;88(5):406-15. |
| 规格 |
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| 单位 |
瓶 |
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