1346704-33-3

• 常用中文名：1-异丙基-N-[(6-甲基-2-氧代-4-丙基-1,2-二氢-3-吡啶基)甲基]-6-[2-(4-甲基-1-哌嗪基)-4-吡啶基]-1H-吲唑-4-甲酰胺
• 常用英文名：GSK343
• CAS号：1346704-33-3
• 分子式：C₃₁H₃₉N₇O₂
• 分子量：541.687
• 相关类别： 生物化工 抑制剂 表观遗传学(Epigenetics) Histone Methyltransferase 抑制剂
• 发布时间：2019-01-02 18:22:45
• 更新时间：2024-01-02 08:15:04
• GSK343 是一种高效,选择性的 EZH2 抑制剂,IC50 为 4 nM。

名称

• 中文名: N-((2-羟基-6-甲基-4-丙基-3-吡啶基)甲基)-1-异丙基-6-(2-(4-甲基-1-哌嗪基)-4-吡啶基)-1H-吲唑-4-甲酰胺
• 英文名: N-((2-hydroxy-6-methyl-4-propylpyridin-3-yl)methyl)-1-isopropyl-6-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-indazole-4-carboxamide
• 中文别名: 1-异丙基-N-[(6-甲基-2-氧代-4-丙基-1,2-二氢-3-吡啶基)甲基]-6-[2-(4-甲基-1-哌嗪基)-4-吡啶基]-1H-吲唑-4-甲酰胺
• 英文别名: 1H-Indazole-4-carboxamide, N-[(1,2-dihydro-6-methyl-2-oxo-4-propyl-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-; 3-methyl-1-(methylethyl)pyrazole-4-carboxylic acid; 1-Isopropyl-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-carboxamide; 1-Isopropyl-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)m ethyl]-6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-c arboxamide; 1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole-4-carboxamide; GSK343; GSK-343

物化性质

• 密度: 1.3±0.1 g/cm3
• 沸点: 797.4±60.0 °C at 760 mmHg
• 分子式: C₃₁H₃₉N₇O₂
• 分子量: 541.687
• 闪点: 436.0±32.9 °C
• 精确质量: 541.316528
• PSA: 99.41000
• LogP: 3.22
• 外观性状: , white to beige to brown
• 蒸汽压: 0.0±2.8 mmHg at 25°C
• 折射率: 1.654
• 储存条件: 2-8°C
• 水溶解性: DMSO: soluble15mg/mL, clear

生物活性

• 描述: GSK343 是一种高效,选择性的 EZH2 抑制剂,IC50 为 4 nM。
• 相关类别:
  信号通路 >> 自噬 >> 自噬
  信号通路 >> 表观遗传学 >> 表观遗传读者域
  信号通路 >> 表观遗传学 >> 组蛋白甲基转移酶
  研究领域 >> 癌症
• 靶点:

  IC50: 4 nM (EZH2), 240 nM (EZH1)[1]

• 体外研究: GSK343在吡啶酮的4-位含有正丙基,其EZH2Kiapp = 1.2±0.2nM。在这项为期6天的增殖试验中,在本研究中评估的细胞系中,前列腺癌细胞系LNCaP对EZH2抑制最敏感,GSK343的生长IC50值为2.9μM[1]。发现GSK343在HeLa细胞中具有13μM的半数抑制浓度值,在SiHa细胞中具有15μM[2]。
• 体内研究: 与对照相比,GSK343(5mg/kg)处理的小鼠显示出显着抑制的肿瘤生长。 GSK343处理组的平均肿瘤体积和重量显着降低。早在植入后20天,相对于对照组,在GSK343处理的群组中观察到肿瘤生长显着减少;这种差异在研究的其余部分持续存在。此外,与对照组相比,异种移植模型中GSK343处理的动物显示E-钙粘蛋白的信使RNA水平显着增加,但波形蛋白信使RNA水平显着降低[2]。
• 激酶实验: 使用5个成员PRC2复合物（Flag-EZH2，EED，SUZ12，AEBP2，RbAp48）评估针对EZH2的活性。测定方案可总结如下：从100％DMSO中的固体制备10mM GSK343原液。以384孔格式（1：3稀释，第6和18列为等体积DMSO对照）制备11点连续稀释母板，并使用声学分配技术分配至测定准备板，以产生100nL GSK343和DMSO对照标记。 。测定添加物由等体积添加的10nM EZH2组成，并且使用多滴组合分配将底物溶液（5μg/ mL HeLa核小体和0.25μM[3H] -SAM）分配到测定板中。将反应板温育1小时，并用等体积添加的含有0.1mM未标记SAM的0.5mg / mL PS-PEI成像珠（RPNQ0098）淬灭。将板密封，暗适应30分钟，并使用Viewlux成像仪获得5分钟终点发光图像。使用ActivityBaseXE分析诸如Z'和背景信号以及剂量响应曲线的平板统计。使用与EZH2相同的384孔SPA测定法评估EZH1的体外生物化学活性作为5成员PRC2复合物的一部分。缓冲组分，试剂分配，GSK343平板制备，淬灭条件和数据分析对于EZH1和EZH2是相同的，最终测定浓度为20nMEZH1,5μg/ mL HeLa核小体和0.25μM[3H] -SAM。进一步的数据分析，pIC50枢轴和可视化由TIBCO Spotfire [1]启用。
• 细胞实验: 为了解释癌细胞系中不同的倍增率，通过检查它们在384孔板中在6天内以大范围的接种密度进行生长，对所有细胞系凭经验确定最佳细胞接种。然后将细胞以最佳接种密度接种并使其粘附过夜。用20点2倍稀释系列的GSK343或0.147％DMSO（载体对照）一式两份处理细胞，并在37℃，5％CO 2中温育6天。然后用每孔25μLCellTiter-Glo裂解细胞，用TECAN Safire2酶标仪定量化学发光。另外，在添加GSK343时（T0）收获未处理的细胞板以定量细胞的起始数。处理6天后的CTG值表示为T0值的百分比，并相对于GSK343浓度作图。数据与4参数方程拟合以产生浓度响应曲线，并确定抑制50％生长所需的GSK343浓度（gIC50）[1]。
• 动物实验: 小鼠[2]使用6周龄雌性裸BALB / c小鼠。为了研究EZH2抑制剂GSK343的作用，在肿瘤体积达到100mm 3后，每隔一天腹膜内注射5mg / kg的100μL磷酸盐缓冲盐水至BALB / c裸鼠（n = 6）。在该分析中，阴性对照组（n = 6）接受盐水。 40天后，杀死小鼠，手术切除皮下肿瘤，称重，拍照，切片，并在10％福尔马林中固定。通过实时逆转录聚合酶链反应测量肿瘤中E-钙粘蛋白，N-钙粘蛋白和波形蛋白的表达水平。
• 参考文献:

  [1]. Sharad K, et al. Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Med Chem Lett. 2012 Oct 19;3(12):1091-6.

  [2]. Ding M, et al. The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer. Clin Exp Pharmacol Physiol. 2015 May;42(5):458-64.

MSDS

SECTION 1: Identification of the substance/mixture and of the company/undertaking Product identifiers Product name: GSK343 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.: 1346704-33-3 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: N-[(1,2-Dihydro-6-methyl-2-oxo-4-propyl-3-pyridinyl)methyl]-1-(1- methylethyl)-6-[2-(4-methyl-1-piperazinyl)-4-pyridinyl]-1H-indazole N-[(6-Methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl]-6-[2-(4- methylpiperazin-1-yl)pyridin-4-yl]-1-(propan-2-yl)-1H-indazole-4 Formula: C31H39N7O2 Molecular Weight: 541,69 g/mol CAS-No.: 1346704-33-3 Hazardous ingredients according to Regulation (EC) No 1272/2008 ComponentClassificationConcentration N-[(1,2-dihydro-6-methyl-2-oxo-4-propyl-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[2-(4-methyl-1- piperazinyl)-4-pyridinyl]-1H-indazole CAS-No.1346704-33-3Acute Tox. 4; H302<= 100 % Hazardous ingredients according to Directive 1999/45/EC ComponentClassificationConcentration N-[(1,2-dihydro-6-methyl-2-oxo-4-propyl-3-pyridinyl)methyl]-1-(1-methylethyl)-6-[2-(4-methyl-1- piperazinyl)-4-pyridinyl]-1H-indazole CAS-No.1346704-33-3Xn, 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 This safety datasheet complies with the requirements of Regulation (EC) No. 1907/2006. Safety, health and environmental regulations/legislation specific for the substance or mixture no data available Chemical Safety Assessment For this product a chemical safety assessment was not carried out SECTION 16: Other information Full text of H-Statements referred to under sections 2 and 3. Acute Tox.Acute toxicity H302Harmful if swallowed. Full text of R-phrases referred to under sections 2 and 3 Xn Harmful R22 Harmful if swallowed. Further information Copyright 2013 Co. LLC. License granted to make unlimited paper copies for internal use only. The above information is believed to be correct but does not purport to be all inclusive and shall be used only as a guide. The information in this document is based on the present state of our knowledge and is applicable to the product with regard to appropriate safety precautions. It does not represent any guarantee of the properties of the product. Corporation and its Affiliates shall not be held liable for any damage resulting from handling or from contact with the above product. See and/or the reverse side of invoice or packing slip for additional terms and conditions of sale.

安全

• 符号: GHS07
• 信号词: Warning
• 危害声明: H302
• 警示性声明: P301 + P312 + P330
• 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