| CAS |
No.127191-97-3 |
| 英文名称 |
KN-62 |
| 分子式 |
C38H35N5O6S2 |
| 分子量 |
721.84 |
| 溶解性 |
Soluble in DMSO ≥10mg/mL |
| 纯度 |
≥98% |
| 外观(性状) |
Light yellow to yellow Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| 运输条件 |
冷藏运输 |
| MDL |
MFCD00083180 |
| SMILES |
CN(C(CC1=CC=C(C=C1)OS(=O)(=O)C2=CC=CC3=C2C=CN=C3)C(=O)N4CCN(CC4)C5=CC=CC=C5)S(=O)(=O)C6=CC=CC7=C6C=CN=C7 |
| InChIKey |
RJVLFQBBRSMWHX-DHUJRADRSA-N |
| InChI |
InChI=1S/C38H35N5O6S2/c1-41(50(45，46)36-11-5-7-29-26-39-19-17-33(29)36)35(38(44)43-23-21-42(22-24-43)31-9-3-2-4-10-31)25-28-13-15-32(16-14-28)49-51(47，48)37-12-6-8-30-27-40-20-18-34(30)37/h2-20，26-27，35H，21-25H2，1H3/t35-/m0/s1 |
| PubChem CID |
5312126 |
| 靶点 |
CaMK;P2X7 |
| 通路 |
Neuronal Signaling;Membrane Transporter&Ion Channel |
| 背景说明 |
KN-62 是一种有效，选择性的钙调蛋白依赖性蛋白激酶 II (CaMK-II)抑制剂，也是非竞争性的 P2X7 受体拮抗剂。 |
| 生物活性 |
KN-62 is a selective and reversible inhibitor of calmodulin-dependent protein kinase II (CaMK-II) with a Ki of 0.9 μM for rat brain CaMK-II. KN-62 directly binds to the calmodulin binding site of CaMK-II. KN-62 displays noncompetitive antagonism at P2X7 receptors in HEK293 cells， with an IC50 value of approximately 15 nM.[1-5] |
| In Vitro |
KN-62 potently antagonizes ATP-stimulated Ba2+ influx into fura-2 loaded human lymphocytes with an IC50 of 12.7 nM and complete inhibition of the flux at a concentration of 500 nM[1].
KN-62 does not inhibit the activity of autophosphorylated Ca2+/CaM kinase II. KN-62 inhibits the Ca2+/calmodulin-dependent autophosphorylation of both alpha (50 kDa) and beta (60 kDa) subunits of Ca2+/CaM kinase II dose dependently in the presence or absence of exogenous substrate[2]. ?
In human leukemic B lymphocytes， KN-62 reduces the rate of permeability increase to larger permeant cations， like ethidium， induced by Bz-ATP with an IC50 of 13.1 nM[4]. |
| In Vivo |
KN62 (5?mg/kg/day; ip; three times a week for 6 weeks) significantly reduces the liver metastatic tumor burden in five weeks old BALB/c athymic nude mice inoculated with TAMR-MCF-7 cells[3].
KN-62 (1 μg/site， i.c.v.) prevents the antidepressant-like behavior and antidepressant-like behaviors of ZnCl2 (10 mg/kg， p.o.)[5]. |
| 细胞实验 |
All experiments are performed using adherent HEK293 cells stably transfected with cDNA encoding the human P2X7 receptor. Adherent cells on 12-well polylysine-coated plates are incubated at 37°C in 1 mL physiological salt solution (125 mM NaCl， 5 mM KCl， 1 mM MgCl2， 1.5 mM CaCl2， 25 mM NaHEPES (pH 7.5)， 10 mM D-glucose， 1 mg/mL BSA). Antagonists(e.g.， KN-62) are added from 1，000× stock solutions dissolved in DMSO. Cells are preincubated with antagonists (e.g.， KN-62) for 15 min prior to stimulation for 10 min with 3 mM ATP (final concentration). Reactions are terminated by rapid aspiration of the extracellular medium in each well. The adherent cells in each well are then extracted overnight with 1 mL 10% HNO3. K+ content in these nitric acid extracts is assayed by atomic absorbance spectrophotometry. Duplicate or triplicate wells are run for all test conditions in each separate experiment[4]. |
| 动物实验 |
Mice[3]
Female Swiss mice (45-55 days old， weighing 30-45 g) are used. The following drugs are used: ZnCl2 (1 or 10 mg/kg)， H-89 (1 μg/site， PKA inhibitor)， KN-62 (1 μg/site， CAMKII inhibitor)， chelerythrine (1 μg/site， PKC inhibitor)， PD98059 (5 μg/site， MAPKK/MEK 1/2 inhibitor)， U0126 (5 μg/site， MEK1/2 inhibitor)， LY294002 (10 nmol/site， PI3K inhibitor)， AR-A014418 (0.001 μg/site， selective GSK-3β inhibitor). ZnCl2 is dissolved in distilled water and administered orally (p.o.). H-89， KN-62， chelerythrine， PD98059， U0126， LY294002， AR-A014418 are dissolved in saline (0.9% NaCl) at a final concentration of 1% dimethyl sulfoxide (DMSO) and administered by intracerebroventricular (i.c.v.) route. The drugs are freshly prepared before treatment and administered in a volume of 10 mL/kg body weight (p.o. route) or 5 μL/site (i.c.v. route). Control animals receive the appropriate vehicle. |
| 激酶实验 |
Lymphocytes (1×107/mL) are cultured with [3H]-oleic acid (2-5 μCi/mL， specific activity 10 Ci/mmol) for 20-24 h in RPMI-1640 medium supplemented with Gentamicin (40 μg/mL)， 10% heat inactivated foetal calf serum (FCS) at 37°C to label membrane phospholipids. Labelled cells are washed twice in HEPES buffered saline followed by a final wash in either HEPES buffered saline or 150 mM KCl medium containing HEPES 10 mM， pH 7.4， bovine serum albumin (BSA) 1 g/L and D-glucose 5 mM and CaCl2 1 mM. Three mL aliquots containing 1.1×107/mL lymphocytes are warmed to 37°C and incubated with or without KN-62 or KN-04 (1 nM-500 nM) for 5 min， then 900 mL aliquots are added to 100 uL butanol (final concentration 30 mM) for a further 5 min， and stimulated with 1 mM ATP for 15 min with gentle mixing in the continued presence of inhibitor or diluent. The phospholipase D reaction is terminated by addition of 1 mL of 20 mM MgCl2 followed by centrifugation and addition of 1 mL ice cold methanol. Membrane lipids are extracted into chloroform/HCl at 4°C under N2， and separated by silica gel thin layer chromatography (t.l.c.) with the solvent system， ethyl acetate/iso-octane/acetic acid/water (13:2:3:10， v/v) under saturating conditions. Sample spots are located by autoradiography and [3H]-phosphatidylbutanol ([3H]-PBut) spots identified by an authentic standard. [3H]-PBut and [3H]-phospholipid spots are scraped into scintillant fluid (PPO in toluene， 4 g/L) and counted in a liquid scintillation counter. The quantity of [3H]-PBut is presented as a percentage of total 3H labelled-cellular phospholipids. Phospholipase D assays are performed in triplicate[1]. |
| 数据来源文献 |
[1]. Gargett CE， et al. The isoquinoline derivative KN-62 a potent antagonist of the P2Z-receptor of human lymphocytes. Br J Pharmacol. 1997 Apr;120(8):1483-90.
[2]. H Hidaka， et al. Pharmacology of protein kinase inhibitors. Annu Rev Pharmacol Toxicol. 1992;32:377-97.
[3]. Miso Park， et al. Involvement of the P2X7 receptor in the migration and metastasis of tamoxifen-resistant breast cancer: effects on small extracellular vesicles production. Sci Rep. 2019 Aug 12;9(1):11587.
[4]. Ravi RG， et al. Potent P2X7 Receptor Antagonists: Tyrosyl Derivatives Synthesized Using a Sequential Parallel Synthetic Approach. Drug Dev Res. 2001 Oct;54(2):75-87.
[5]. Manosso LM， et al. Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Jun 3;59:59-67. |
| 规格 |
1mg 5mg 10mg 50mg |
| 单位 |
瓶 |
中文
英语
说明书下载
京公网安备 11011202000391号