5-[2,4-Dihydroxy-6-(4-nitrophenoxy)phenyl]-N-(1-methyl-4-piperidinyl)-3-isoxazolecarboxamide
5-[2,4-Dihydroxy-6-(4-nitrophenoxy)phenyl]-N-(1-methyl-4-piperidinyl)-3-isoxazolecarboxamide Basic information
- Product Name:
- 5-[2,4-Dihydroxy-6-(4-nitrophenoxy)phenyl]-N-(1-methyl-4-piperidinyl)-3-isoxazolecarboxamide
- Synonyms:
-
- NMS-E973
- 5-[2,4-Dihydroxy-6-(4-nitrophenoxy)phenyl]-N-(1-methyl-4-piperidinyl)-3-isoxazolecarboxamide
- 3-Isoxazolecarboxamide, 5-[2,4-dihydroxy-6-(4-nitrophenoxy)phenyl]-N-(1-methyl-4-piperidinyl)-
- 5-[2,4-Dihydroxy-6-(4-nitrophenoxy)phenyl]-N-(1-methyl-4-piperidinyl)-3-isoxazolecarboxamide USP/EP/BP
- NMS-E973,Leukemia,NMS E973,inhibit,HSP,Heat shock proteins,Adenocarcinoma,Hsp90α,ovary,colon,breast,cancer,Carcinoma,Neuroblastoma,NMSE973,NMS-E-973,Melanoma,Inhibitor
- 5-(2,4-Dihydroxy-6-(4-nitrophenoxy)phenyl)-N-(1-methylpiperidin-4-yl)isoxazole-3-carboxamide
- NMS-E973, 10 mM in DMSO
- CAS:
- 1253584-84-7
- MF:
- C22H22N4O7
- MW:
- 454.43
- Product Categories:
-
- Inhibitors
- Mol File:
- 1253584-84-7.mol
5-[2,4-Dihydroxy-6-(4-nitrophenoxy)phenyl]-N-(1-methyl-4-piperidinyl)-3-isoxazolecarboxamide Chemical Properties
- Boiling point:
- 686.9±55.0 °C(Predicted)
- Density
- 1.50±0.1 g/cm3(Predicted)
- storage temp.
- Store at -20°C
- solubility
- Soluble in DMSO
- form
- Powder
- pka
- 5.69±0.20(Predicted)
- color
- Off-white to yellow
5-[2,4-Dihydroxy-6-(4-nitrophenoxy)phenyl]-N-(1-methyl-4-piperidinyl)-3-isoxazolecarboxamide Usage And Synthesis
Uses
NMS-E973 is a potent and selective inhibitor of HSP90. NMS-E973 binds to the ATP binding site of Hsp90α with a DC50 of <10 nM. NMS-E973 is able to cross the blood-brain barrier (BBB). Antitumor efficacy[1].
Biological Activity
nms-e973 is a potent and selective inhibitor of heat shock protein 90 (hsp90) with dc50 value of < 10nm [1].since hsp90 plays an important role in the conformational maturation, stability and function of some oncogenic proteins, the inhibitors of hsp90 are developed as therapeutic for cancers. nms-e973 is a selective inhibitor of hsp90. it binds to hsp90α within the atp binding site with dc50 value of < 10nm. besides that, nms-e973 shows no effect on a panel of 52 various protein kinases such as abl, ack1, akt1 and alk. the ic50 value of it for hsc70 is > 10μm. nms-e973 exerts antiproliferation effects on a2780 tumor cell line and bt-474 breast cancer cell line with ic50 values of 69nm and 110nm, respectively. when treated with mice bearing a2780 xenografts, the intravenous administration of nms-e973 significantly inhibits tumor growth with tgi value of 53% at dose of 30mg/kg. moreover, nms-e973 also displays antitumor activity in tumors resistant to kinase inhibitors such as vemurafenib [1, 2].
in vivo
NMS-E973 (60 mg/kg; i.v.) inhibits the growth of A375 tumors subcutaneously or intracranially implanted in mice[1].
NMS-E973 exhibits moderate elimination half-lives (5.55±1.07 h) due to high plasma clearance (39.9±1.70 mL/min/kg) combined with large volumes of distribution (5.83±3.18 L/kg) following intravenous administration (10 mg/kg) in mice[1].
| Animal Model: | Balb/c male nude mice (aged 6 to 8 weeks) xenografted with the A375 tumors[1] |
| Dosage: | 60 mg/kg |
| Administration: | Administered twice daily i.v. according to 2 schedules: (i) every other day for 12 days and (ii) 3 days on/1 day off/3 days on (3-1-3, one cycle). |
| Result: | Both schedules resulted in tumor shrinkage and TGI of 74% and 89%, respectively. |
target
Hsp90
IC 50
HSP90α: 10 nM (DC50)
References
[1] brasca m g, mantegani s, amboldi n, et al. discovery of nms-e973 as novel, selective and potent inhibitor of heat shock protein 90 (hsp90). bioorganic & medicinal chemistry, 2013, 21(22): 7047-7063.
[2] fogliatto g, gianellini l, brasca m g, et al. nms-e973, a novel synthetic inhibitor of hsp90 with activity against multiple models of drug resistance to targeted agents, including intracranial metastases. clinical cancer research, 2013, 19(13): 3520-3532.
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