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1431612-23-5生产厂家

1431612-23-5价格

1431612-23-5

1431612-23-5结构式
1431612-23-5结构式

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中文名 N-[(1,2-二氢-6-甲基-2-氧代-4-丙基-3-吡啶基)甲基]-1-(1-甲基乙基)-6-[6-[4-(1-甲基乙基)-1-哌嗪基]-3-吡啶基]-1H-吲唑-4-甲酰胺
英文名 N-[(6-methyl-2-oxo-4-propyl-1H-pyridin-3-yl)methyl]-1-propan-2-yl-6-[6-(4-propan-2-ylpiperazin-1-yl)pyridin-3-yl]indazole-4-carboxamide
英文别名 s7165
1-Isopropyl-6-[6-(4-isopropyl-1-piperazinyl)-3-pyridinyl]-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide
unc1999
1H-Indazole-4-carboxamide, N-[(1,2-dihydro-6-methyl-2-oxo-4-propyl-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[6-[4-(1-methylethyl)-1-piperazinyl]-3-pyridinyl]-
描述 UNC1999 是一种有效,选择性和SAM-竞争性的 EZH2 和 EZH1 抑制剂,IC50 分别为 10 nM 和 45 nM。
相关类别
靶点

IC50: <10 nM (EZH2), 45 nM (EZH1)[1]

体外研究 UNC1999,第一种口服生物可利用的抑制剂,对野生型和突变型EZH2以及EZH1具有高体外效力,EZH1是一种密切相关的H3K27甲基转移酶,在各自的催化结构域中与EZH2具有96%的序列同一性。 UNC1999对EZH2和EZH1具有高选择性,适用于广泛的表观遗传和非表观遗传靶标,与辅因子SAM竞争,与肽底物无竞争性。对于sigma1,sigma2,组胺H3和NET(去甲肾上腺素转运蛋白),UNC1999的Ki值分别为4,700 nM,65 nM,300 nM和1,500 nM。 NC1999选择性地杀死DB细胞,即具有EZH2 Y641N突变的DLBCL细胞系。 UNC1999显示DB细胞增殖的浓度和时间依赖性抑制(EC50 = 633±101nM(n = 3))[1]。
体内研究 以15,50或150mg/kg单次腹膜内(IP)注射UNC1999获得高C max(9,700-11,800nM)并且在雄性瑞士白化小鼠中表现出剂量线性。在整个24小时内,150和50mg/kg IP剂量均导致UNC1999的血浆浓度高于其细胞IC50,而15mg/kg IP剂量导致UNC1999的血浆浓度高于其细胞IC50约12小时。 。我们接下来检查了UNC1999是否是口服生物可利用的,并且很高兴地发现单个50mg/kg口服剂量的UNC1999在雄性瑞士白化小鼠中达到高Cmax(4,700nM)和良好的暴露水平。在单次口服剂量后,UNC1999的血浆浓度维持在其细胞IC50以上约20小时。值得注意的是,所有测试小鼠都能很好地耐受包括150 mg/kg IP剂量在内的所有剂量,并且没有观察到不良反应[1]。
激酶实验 产生EZH2 Y641N突变体并通过BPS Bioscience进行测定。在HMT测定缓冲液中用10%DMSO制备一系列UNC1999稀释液,并将5μL稀释液加入到50μL反应中,使得DMSO的最终浓度在所有反应中均为1%。所有酶促反应在室温下一式两份进行60分钟(EZH2)和180分钟(EZH2 Y641N)在含有HMT测定缓冲液,S-腺苷甲硫氨酸,酶和UNC1999的50μL混合物中进行。这些50μL反应在HMT基底预涂板的孔中进行。酶促反应后,弃去反应混合物,用TBST缓冲液洗涤每个孔三次,并用封闭缓冲液缓慢摇动10分钟。将孔清空,并加入100μL稀释的1°抗体。然后将板在室温下缓慢摇动60分钟。如前所述,将板清空并洗涤三次,并在室温下与封闭缓冲液一起摇动10分钟。弃去封闭缓冲液后,加入100μL稀释的2°抗体。然后将板在室温下缓慢摇动30分钟。如前所述,将板清空并洗涤三次,并在室温下与封闭缓冲液一起摇动10分钟。弃去封闭缓冲液,新制备HRP化学发光底物的混合物。将100μL该混合物加入每个空孔中。立即,在BioTek SynergyTM 2酶标仪[1]中测量样品的发光。
细胞实验 DB细胞是一种含有EZH2 Y641N突变的弥漫性大B细胞淋巴瘤细胞系,来自ATCC,并在补充有10%胎牛血清,抗生素和各种浓度的UNC1999(0.1,0.2,0.3, 0.4,0.5,1,2,3和5μM)或UNC2400和DMSO对照。含有试验化合物或对照的培养基每三天更新一次。使用TC20自动细胞计数器系统测量来自至少三次独立实验的活细胞数。使用酸性提取方案从细胞核制备总组蛋白。使用15%的SDS-PAGE分离约1微克的总组蛋白,转移至PVDF膜,并用组蛋白抗体探测。本研究中使用的抗体是针对EZH2,一般H3和H3K27me3的抗体[1]。
动物实验 小鼠[1]使用Sai Life Sciences的雄性瑞士白化小鼠进行标准PK研究。评估UNC1999的四个剂量(15,50和150mg / kg IP,和50mg / kg PO)。每项研究持续24小时。在八个时间点(给药后0.08,0.25,0.5,1,2,4,8和24小时)中报告的UNC1999的血浆浓度是来自3只试验动物的平均值。
参考文献

[1]. Konze KD, et al. An Orally Bioavailable Chemical Probe of the Lysine Methyltransferases EZH2 and EZH1. ACS Chem Biol. 2013;8(6):1324-34.

密度 1.2±0.1 g/cm3
沸点 804.7±65.0 °C at 760 mmHg
分子式 C33H43N7O2
分子量 569.740
闪点 440.4±34.3 °C
精确质量 569.347839
PSA 99.41000
LogP 4.17
外观性状 white to beige
蒸汽压 0.0±2.9 mmHg at 25°C
折射率 1.643
储存条件 2-8°C
水溶解性 DMSO: soluble15mg/mL, clear

SECTION 1: Identification of the substance/mixture and of the company/undertaking
Product identifiers
Product name: UNC1999
REACH No.: A registration number is not available for this substance as the substance
or its uses are exempted from registration, the annual tonnage does not
require a registration or the registration is envisaged for a later
registration deadline.
CAS-No.: 1431612-23-5
Relevant identified uses of the substance or mixture and uses advised against
Identified uses: Laboratory chemicals, Manufacture of substances



SECTION 2: Hazards identification
Classification of the substance or mixture
Classification according to Regulation (EC) No 1272/2008
Acute toxicity, Oral (Category 4), H302
For the full text of the H-Statements mentioned in this Section, see Section 16.
Classification according to EU Directives 67/548/EEC or 1999/45/EC
Xn HarmfulR22
For the full text of the R-phrases mentioned in this Section, see Section 16.
Label elements
Labelling according Regulation (EC) No 1272/2008
Pictogram
Signal wordWarning
Hazard statement(s)
H302Harmful if swallowed.
Precautionary statement(s)none
Supplemental Hazardnone
Statements
Other hazards - none

SECTION 3: Composition/information on ingredients
Substances
Synonyms: 1-Isopropyl-6-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-N-((6-methyl-2-
oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-
Formula: C33H43N7O2
Molecular Weight: 569,74 g/mol
CAS-No.: 1431612-23-5
Hazardous ingredients according to Regulation (EC) No 1272/2008
ComponentClassificationConcentration
1-isopropyl-6-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-N-((6-methyl-2-oxo-4-propyl-1,2-
dihydropyridin-3-yl)methyl)-1H-indazole-4-
CAS-No.1431612-23-5Acute Tox. 4; H302<= 100 %
Hazardous ingredients according to Directive 1999/45/EC
ComponentClassificationConcentration
1-isopropyl-6-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-N-((6-methyl-2-oxo-4-propyl-1,2-
dihydropyridin-3-yl)methyl)-1H-indazole-4-
CAS-No.1431612-23-5Xn, R22<= 100 %
For the full text of the H-Statements and R-Phrases mentioned in this Section, see Section 16

SECTION 4: First aid measures
Description of first aid measures
General advice
Consult a physician. Show this safety data sheet to the doctor in attendance.
If inhaled
If breathed in, move person into fresh air. If not breathing, give artificial respiration. Consult a physician.
In case of skin contact
Wash off with soap and plenty of water. Consult a physician.
In case of eye contact
Flush eyes with water as a precaution.
If swallowed
Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician.
Most important symptoms and effects, both acute and delayed
The most important known symptoms and effects are described in the labelling (see section 2.2) and/or in
section 11
Indication of any immediate medical attention and special treatment needed
no data available

SECTION 5: Firefighting measures
Extinguishing media
Suitable extinguishing media
Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Special hazards arising from the substance or mixture
Carbon oxides, nitrogen oxides (NOx)
Advice for firefighters
Wear self contained breathing apparatus for fire fighting if necessary.
Further information
no data available

SECTION 6: Accidental release measures
Personal precautions, protective equipment and emergency procedures
Use personal protective equipment. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure
adequate ventilation. Avoid breathing dust.
For personal protection see section 8.
Environmental precautions
Do not let product enter drains.
Methods and materials for containment and cleaning up
Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed
containers for disposal.
Reference to other sections
For disposal see section 13.

SECTION 7: Handling and storage
Precautions for safe handling
Avoid contact with skin and eyes. Avoid formation of dust and aerosols.
Provide appropriate exhaust ventilation at places where dust is formed.
For precautions see section 2.2.
Conditions for safe storage, including any incompatibilities
Store in cool place. Keep container tightly closed in a dry and well-ventilated place.
Recommended storage temperature: 2 - 8 °C
Specific end use(s)
A part from the uses mentioned in section 1.2 no other specific uses are stipulated

SECTION 8: Exposure controls/personal protection
Control parameters
Components with workplace control parameters
Exposure controls
Appropriate engineering controls
Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and
at the end of workday.
Personal protective equipment
Eye/face protection
Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested
and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
Skin protection
Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique
(without touching glove's outer surface) to avoid skin contact with this product. Dispose of
contaminated gloves after use in accordance with applicable laws and good laboratory practices.
Wash and dry hands.
The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and
the standard EN 374 derived from it.
Body Protection
Complete suit protecting against chemicals, The type of protective equipment must be selected
according to the concentration and amount of the dangerous substance at the specific workplace.
Respiratory protection
For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher
level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges.
Use respirators and components tested and approved under appropriate government standards
such as NIOSH (US) or CEN (EU).
Control of environmental exposure
Do not let product enter drains.

SECTION 9: Physical and chemical properties
Information on basic physical and chemical properties
a) AppearanceForm: solid
b) Odourno data available
c) Odour Thresholdno data available
d) pHno data available
e) Melting point/freezingno data available
point
f) Initial boiling point and no data available
boiling range
g) Flash pointno data available
h) Evapouration rateno data available
i) Flammability (solid, gas) no data available
j) Upper/lowerno data available
flammability or
explosive limits
k) Vapour pressureno data available
l) Vapour densityno data available
m) Relative densityno data available
n) Water solubilityno data available
o) Partition coefficient: n- no data available
octanol/water
p) Auto-ignitionno data available
temperature
q) Decompositionno data available
temperature
r) Viscosityno data available
s) Explosive propertiesno data available
t) Oxidizing propertiesno data available
Other safety information
no data available

SECTION 10: Stability and reactivity
Reactivity
no data available
Chemical stability
Stable under recommended storage conditions.
Possibility of hazardous reactions
no data available
Conditions to avoid
no data available
Incompatible materials
Strong oxidizing agents
Hazardous decomposition products
Other decomposition products - no data available
In the event of fire: see section 5

SECTION 11: Toxicological information
Information on toxicological effects
Acute toxicity
no data available
Skin corrosion/irritation
no data available
Serious eye damage/eye irritation
no data available
Respiratory or skin sensitisation
no data available
Germ cell mutagenicity
no data available
Carcinogenicity
IARC:No component of this product present at levels greater than or equal to 0.1% is identified as
probable, possible or confirmed human carcinogen by IARC.
Reproductive toxicity
no data available
Specific target organ toxicity - single exposure
no data available
Specific target organ toxicity - repeated exposure
no data available
Aspiration hazard
no data available
Additional Information
RTECS: Not available
To the best of our knowledge, the chemical, physical, and toxicological properties have not been
thoroughly investigated.

SECTION 12: Ecological information
Toxicity
no data available
Persistence and degradability
no data available
Bioaccumulative potential
no data available
Mobility in soil
no data available
Results of PBT and vPvB assessment
PBT/vPvB assessment not available as chemical safety assessment not required/not conducted
Other adverse effects
no data available

SECTION 13: Disposal considerations
Waste treatment methods
Product
Offer surplus and non-recyclable solutions to a licensed disposal company. Dissolve or mix the material
with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber.
Contaminated packaging
Dispose of as unused product.

SECTION 14: Transport information
UN number
ADR/RID: -IMDG: -IATA: -
UN proper shipping name
ADR/RID: Not dangerous goods
IMDG: Not dangerous goods
IATA:Not dangerous goods
Transport hazard class(es)
ADR/RID: -IMDG: -IATA: -
Packaging group
ADR/RID: -IMDG: -IATA: -
Environmental hazards
ADR/RID: noIMDG Marine pollutant: noIATA: no
Special precautions for user
no data available



SECTION 15 - REGULATORY INFORMATION
N/A


SECTION 16 - ADDITIONAL INFORMATION
N/A
符号 GHS07
GHS07
信号词 Warning
危害声明 H302
危害码 (欧洲) Xn
风险声明 (欧洲) 22
危险品运输编码 NONH for all modes of transport