MK-8776(SCH-900776)
(Synonyms: 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,MK-8776) 目录号 : GC16374
MK-8776(SCH-900776) 是一种新型、选择性更高的Chk1抑制剂，旨在通过废除细胞周期阻滞来增强DNA损伤剂和抗代谢物的细胞毒性。
Cas No.:891494-63-6
Sample solution is provided at 25 µL, 10mM.
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MK-8776(SCH-900776) is a novel and more selective Chk1 inhibition, developed to enhance the cytotoxicity of DNA-damaging agents and antimetabolites by abrogating cell cycle arrest[1][2].
In vitro, MK-8776 (3μM) pretreated p53⁻/⁻, p21⁻/⁻, PTEN⁻/⁻ human colon cancer HCT116 cells for 2h followed by 48–72h of co-treatment with cisplatin (20μM) or LA-12 (0.75μM). MK-8776 enhanced human colon cancer cell sensitivity to the cytotoxic effects of cisplatin and LA-12 complexes and resulted in apparent increase in G1/S phase–related apoptosis, stimulation of mitotic slippage, and senescence of HCT116 cells[3]. MK-8776 (200nM) treatment on p53-defective human non-small lung cancer (NSCLC) cells and head and neck squamous cell carcinomas (HNSCC) for 1h prior to irradiation and 18h post-irradiation radiosensitized NSCLC and HNSCC lines, reduced their clonogenic survival and increased mitotic entry with unrepaired DNA double-strand breaks[4].
In vivo, MK-8776 (50mg/kg) was administrated i.p. alone twice a week or in combinations with olaparib (50mg/kg) into olaparib-resistant patient-derived xenograft (PDX) models of high-grade serous ovarian cancer (HGSOC) over a period of up to 37 days. MK-8776 showed minimal antitumor activity and significantly reduced tumor growth in combination with olaparib[5]. MK-8776 (5mg/kg) plus enzalutamide (20mg/kg) administration into androgen receptor-positive triple-negative breast cancer (AR+TNBC+) mouse model every other day for two weeks showed the significant tumor growth suppression, with enhanced DNA damage (increased γ-H2AX) and reduced proliferation (decreased Ki-67)[6]. MK-8776 (16-32mg/kg) was administered intraperitoneally into nude mice bearing A2780 ovarian xenografts in combination with gemcitabine (150mg/kg). Dose escalation of MK-8776 induced incremental improvements in tumor regression[7].
References:
[1] Montano R, Chung I, Garner K M, Parry D, Eastman A. Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites. Mol Cancer Ther. 2012 Feb;11(2):427-38.
[2] Melia E, Fisch A S, Tinhofer I, Parsons J L. Targeting Chk1 and Wee1 kinases enhances radiosensitivity of 2D and 3D head and neck cancer models to X-rays and low/high-LET protons. Cell Death Dis. 2025 Feb 25;16(1):128.
[3] Herůdková J, Paruch K, Khirsariya P, et al. Chk1 Inhibitor SCH900776 Effectively Potentiates the Cytotoxic Effects of Platinum-Based Chemotherapeutic Drugs in Human Colon Cancer Cells.Neoplasia. 2017 Oct;19(10):830-841.
[4] Bridges K A, Chen X X, Liu H F, et al. MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells.Oncotarget. 2016 Nov 1;7(44):71660-71672.
[5] Biegała L, Statkiewicz M, Gajek A, et al. Molecular mechanisms restoring olaparib efficacy through ATR/CHK1 pathway inhibition in olaparib-resistant BRCA1/2MUT ovarian cancer models. Biochim Biophys Acta Mol Basis Dis. 2025 Feb;1871(2):167574.
[6] Gao F Y, Wu Y Y, Wang R T, et al. Precise nano-system-based drug delivery and synergistic therapy against androgen receptor-positive triple-negative breast cancer.Acta Pharm Sin B. 2024 Jun;14(6):2685-2697.
[7] Guzi T J, Paruch K, Dwyer M P, et al. Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther. 2011 Apr;10(4):591-602.
MK-8776(SCH-900776) 是一种新型、选择性更高的Chk1抑制剂，旨在通过废除细胞周期阻滞来增强DNA损伤剂和抗代谢物的细胞毒性[1][2]。
体外实验中，MK-8776 (3μM) 预处理p53⁻/⁻、p21⁻/⁻、PTEN⁻/⁻人结肠癌HCT116细胞2h后，与顺铂(20μM)或LA-12(0.75μM)联合处理48–72h，可显著增强结肠癌细胞对顺铂及LA-12复合物毒性的敏感性，导致G1/S期相关凋亡明显增加，促进有丝分裂滑移并诱导HCT116细胞衰老[3]。MK-8776 (200nM) 于照射前1h处理p53缺陷的人非小细胞肺癌 (NSCLC) 细胞及头颈鳞癌 (HNSCC) 细胞，并持续至照后18h，可显著增强NSCLC与HNSCC细胞的放射敏感性，降低其克隆形成率，增加未修复DNA双链断裂下的有丝分裂进入[4]。
体内实验中，MK-8776 (50mg/kg) 每周两次腹腔注射单用或与olaparib (50mg/kg) 联合，用于olaparib耐药的高级别浆液性卵巢癌 (HGSOC) 患者来源异种移植 (PDX) 模型，最长观察37天；MK-8776单药抗肿瘤活性微弱，但与olaparib联用可显著抑制肿瘤生长[5]。MK-8776 (5mg/kg) 联合enzalutamide (20mg/kg) 隔日给药于雄激素受体阳性三阴性乳腺癌 (AR+TNBC+) 小鼠模型，持续两周，可显著抑制肿瘤生长，DNA损伤标志 (γ-H2AX升高) 增强，增殖标志 (Ki-67降低) 减少[6]。MK-8776 (4-32mg/kg) 与gemcitabine (150mg/kg) 联合腹腔注射于A2780卵巢癌裸鼠异种移植模型，随MK-8776剂量递增，肿瘤退缩程度逐步改善[7]。
| Cell experiment [1]: | |
Cell lines | Human non-small lung cancer (NSCLC) cells and head and neck squamous cell carcinomas (HNSCC) |
Preparation Method | Cells were treated for 1h with 200nM MK-8776 prior to irradiation. After irradiation, the cells were incubated for an additional 18h post-irradiation treatment with 200nM MK-8776. |
Reaction Conditions | 200nM; 1h prior and 18h after irradiation |
Applications | MK-8776 consistently radiosensitized p53-defective NSCLC and HNSCC lines, reducing their clonogenic survival and increasing mitotic entry with unrepaired DNA double-strand breaks. |
| Animal experiment [2]: | |
Animal models | Female nude mice |
Preparation Method | Animals were randomized to treatment groups and treated intraperitoneally with the threshold dose of MK-8776 associated with intratumoral induction of g-H2AX was then determined in established A2780 ovarian xenografts in combination with 150mg/kg gemcitabine. |
Dosage form | 16-32mg/kg; i.p.; 30min after gemcitabine |
Applications | Dose escalation of MK-8776 induced incremental improvements in tumor regression. |
References: | |
| Cas No. | 891494-63-6 | SDF | |
| 别名 | 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,MK-8776 | ||
| 化学名 | (R)-6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-5-(piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine | ||
| Canonical SMILES | BrC(C([C@@H]1CCCNC1)=N2)=C(N)N3C2=C(C4=CN(C)N=C4)C=N3 | ||
| 分子式 | C15H18BrN7 | 分子量 | 376.25 |
| 溶解度 | ≥ 18.8mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.6578 mL | 13.289 mL | 26.5781 mL |
| 5 mM | 531.6 μL | 2.6578 mL | 5.3156 mL |
| 10 mM | 265.8 μL | 1.3289 mL | 2.6578 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
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