6-溴-3-(1-甲基-1H-吡唑-4-基)-5-(3R)-3-哌啶基吡唑并[1,5-a]嘧啶-7-胺

中文名	MK-8776 (SCH 900776)
英文名	MK-8776 (SCH 900776)
别名	化合物MK-8776 SCH900776(S型) SCH900776(R型) 6-溴-3-(1-甲基-1H-吡唑-4-基)-5-(3R)-3-哌啶基吡唑并[1,5-A]嘧啶-7-胺
英文别名	MK-8776. SCH900776 SCH-900776 SCH 900776 SCH900776(R) MK-8776 (SCH 900776) SCH 900776 (MK-8776) 6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(3R)-3-piperidinylpyrazolo[1,5-a]pyrimidin-7-amine 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-((R)-piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine (R)-6-Bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine
CAS	891494-63-6
化学式	C15H18BrN7
分子量	376.25
密度	1.80
溶解度	溶于DMSO，不溶于水
酸度系数	8.88±0.10(Predicted)
存储条件	-20℃
体外研究	SCH 900776 is not a potent inhibitor of Chk2 and CDK2 with IC50 of 1.5 μM and 0.16 μM, respectively. SCH 900776 shows no significant inhibition of cytochrome P450 human liver microsomal isoforms 1A2, 2C9, 2C19, 2D6, and 3A4. SCH 900776 induces a dose-dependent loss of DNA replication capability 24 hours after hydroxyurea exposure. SCH 900776 enhances the γ-H2AX response of hydroxyurea, 5-fluoruracil, and cytarabine. In combination with an antimetabolite, SCH 900776 induces accumulation of γ-H2AX within 2 hours, indicative of replication fork collapse and double stranded DNA breaks. Additionally, SCH 900776 suppresses accumulation of the Chk1 pS296 autophosphorylation in a dose-dependent manner. Exposure of proliferating WS1 cells to SCH 900776 is associated with rapid, dose-dependent accumulation of Chk1 pS345, indicating that cycling populations of normal cells induce Chk1 pS345 following exposure to SCH 900776 as part of a futile cycle, perhaps driven by AT-family kinases and DNA-PK. SCH 900776是Chk2和CDK2的低效抑制剂，IC50分别为1.5 μM 和 0.16 μM。SCH 900776对细胞色素P450人肝微粒体亚型1A2，2C9，2C19，2D6，和3A4没有显著的抑制作用。羟基脲下暴露24小时后，SCH 900776诱导DNA复制能力剂量依赖性损失。SCH 900776增强γ-H2AX对羟基脲，5-氟尿嘧啶，和阿糖孢苷的响应。与抗代谢物结合，SCH 900776在2小时内诱导γ-H2AX的累积，表明复制叉瓦解，并且双链DNA断裂。此外，SCH 900776以剂量依赖的方式抑制Chk1 pS296自磷酸化的积累。增殖的WS1细胞暴露于SCH 900776，与Chk1 pS345快速的，剂量依赖性聚集相关，表明正常细胞的循环群诱导Chk1 pS345在暴露于SCH 900776后，是一部分无效循环，这也许通过AT-家族激酶和DNA-PK驱动。
体内研究	Administered 30 minutes after gemcitabine, 4 mg/kg SCH 900776 is sufficient to induce the γ-H2AX biomarker while 8 mg/kg leads to enhanced tumor pharmacodynamic and regression responses relative to gemcitabine or SCH 900776 alone. Dose escalation of SCH 900776 (16 mg/kg and 32 mg/kg) induces incremental improvements in tumor response. Importantly, doses of SCH 900776 associate with robust biomarker activation and improved tumor response are not associated with enhanced toxicity of gemcitabine on hematological parameters in BALB/c mice. 相对于gemcitabine或SCH 900776单独给药，Gemcitabine给药30分钟后，4 mg/kg SCH 900776足以诱导γ-H2AX生物标志物，而8 mg/kg增强肿瘤药效动力学和退化响应。递增剂量的SCH 900776 (16 mg/kg和32 mg/kg)诱导肿瘤响应持续改进。重要的是，在BALB/c 小鼠体内，SCH 900776的剂量与强的生物标志物活化相关，而提高的肿瘤响应与gemcitabine对血液学指标增强的毒性无关。
参考资料展开查看	1: Sakurikar N, Eastman A. Will targeting Chk1 have a role in the future of cancer therapy? J Clin Oncol. 2015 Mar 20;33(9):1075-7. doi: 10.1200/JCO.2014.60.0767. Epub 2015 Feb 17. PubMed PMID: 25691674. 2: Daud AI, Ashworth MT, Strosberg J, Goldman JW, Mendelson D, Springett G, Venook AP, Loechner S, Rosen LS, Shanahan F, Parry D, Shumway S, Grabowsky JA, Freshwater T, Sorge C, Kang SP, Isaacs R, Munster PN. Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors. J Clin Oncol. 2015 Mar 20;33(9):1060-6. doi: 10.1200/JCO.2014.57.5027. Epub 2015 Jan 20. PubMed PMID: 25605849. 3: Lv M, Ma S, Tian Y, Zhang X, Lv W, Zhai H. Computational studies on the binding mechanism between triazolone inhibitors and Chk1 by molecular docking and molecular dynamics. Mol Biosyst. 2015 Jan;11(1):275-86. doi: 10.1039/c4mb00449c. Epub 2014 Nov 5. PubMed PMID: 25372494.

6-溴-3-(1-甲基-1H-吡唑-4-基)-5-(3R)-3-哌啶基吡唑并[1,5-a]嘧啶-7-胺 - 配置溶液浓度参考

	1mg	5mg	10mg
1 mM	2.658 ml	13.289 ml	26.578 ml
5 mM	0.532 ml	2.658 ml	5.316 ml
10 mM	0.266 ml	1.329 ml	2.658 ml
5 mM	0.053 ml	0.266 ml	0.532 ml

最后更新：2024-01-02 23:10:35

6-溴-3-(1-甲基-1H-吡唑-4-基)-5-(3R)-3-哌啶基吡唑并[1,5-a]嘧啶-7-胺

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产品名: 6-溴-3-(1-甲基-1H-吡唑-4-基)-5-(3R)-3-哌啶基吡唑并[1,5-a]嘧啶-7-胺去供应商网站查看询盘
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产品描述: 中文名：6-溴-3-(1-甲基-1H-吡唑-4-基)-5-(3R)-3-哌啶基吡唑并[1,5-a]嘧啶-7-胺英文名:MK-8776 (SCH 900776) 更多

上海麦克林生化科技股份有限公司

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CAS: 891494-63-6
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上海源叶生物科技有限公司

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