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]。