MK-4827

MK-4827 is an orally active PARP inhibitor that simultaneously inhibits both PARP1 (IC₅₀=3.8nM) and PARP2 (IC₅₀=2.1nM). MK-4827 blocks DNA repair by inhibiting PARP enzyme activity, thereby inducing cancer cell death^[1-2]. MK-4827 is used in research for the treatment of various types of cancer^[3-4].

In vitro, treatment of ovarian cancer OVCAR8 cells and pancreatic cancer MIA PaCa-2 cells with MK-4827 (10-20μM) for 48 to 72 hours, MK-4827 significantly suppressed STAT3 phosphorylation, induced apoptosis, downregulated the expression of the anti-apoptotic gene BCL2L1, and upregulated the expression of the pro-apoptotic genes CASP3, CASP8, and CASP9^[5]. In esophageal squamous cell carcinoma KYSE-30 and KYSE-150 cells, treatment with MK-4827 (5μM) combined with radiotherapy (4Gy) for 24 hours, MK-4827 markedly enhanced radiation-induced DNA double-strand break damage (increased γ-H2AX expression) and promoted apoptosis, while also increasing radiosensitivity by inhibiting FANCG expression^[6].

In vivo, in an ovarian cancer peritoneal metastasis model, oral administration of MK-4827 (50mg/kg) to tumor-bearing mice (inoculated with ID8 cells or patient-derived xenografts) three times per week for 3-8 weeks, starting from day 3 or 6 post-inoculation, MK-4827 significantly inhibited tumor growth, reduced the number of abdominal lesions and ascites volume, and induced ferroptosis in tumor cells^[7]. In an atherosclerosis model, oral administration of MK-4827 (10mg/kg) to high-fat diet-fed ApoE⁻/⁻ or Ldlr⁻/⁻ mice three times per week for 8-12 weeks, starting from week 4 or 16 of dietary intervention, MK-4827 significantly reduced atherosclerotic plaque burden, decreased necrotic core area, increased fibrous cap thickness, and suppressed phenotypic switching of smooth muscle cells^[8].

References:
[1] Jones P, Altamura S, Boueres J, et al. Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): a novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J Med Chem. 2009 Nov 26;52(22):7170-85.
[2] Bridges KA, Toniatti C, Buser CA, et al. Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. Oncotarget. 2014 Jul 15;5(13):5076-86.
[3] Wang L, Mason KA, Ang KK, et al. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest New Drugs. 2012 Dec;30(6):2113-20.
[4] Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016 Dec 1;375(22):2154-2164.
[5] Zhao Q, Kohut A, Li YJ, et al. Niraparib-induced STAT3 inhibition increases its antitumor effects. Front Oncol. 2022 Oct 17;12:966492.
[6] Cui Y, Huang W, Du F, et al. Therapeutic benefits of niraparib tosylate as radio sensitizer in esophageal squamous cell carcinoma: an in vivo and in vitro preclinical study. Clin Transl Oncol. 2022 Aug;24(8):1643-1656.
[7] Jin N, Qian YY, Jiao XF, et al. Niraparib restricts intraperitoneal metastases of ovarian cancer by eliciting CD36-dependent ferroptosis. Redox Biol. 2025 Mar;80:103528.
[8] Pan H, Ho SE, Xue C, et al. Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease. Circulation. 2024 Jun 11;149(24):1885-1898.

MK-4827是具有口服活性的PARP抑制剂，可同时抑制PARP1（IC₅₀=3.8nM）和PARP2（IC₅₀=2.1nM），MK-4827可抑制PARP酶来阻断DNA修复，诱导癌细胞死亡^[1-2]。MK-4827被用于多种癌症治疗的相关研究中^[3-4]。

在体外，MK-4827（10-20μM）处理卵巢癌OVCAR8细胞和胰腺癌MIA PaCa-2细胞48小时或72小时，MK-4827显著抑制STAT3磷酸化水平，并诱导细胞凋亡，同时下调抗凋亡基因BCL2L1表达并上调促凋亡基因CASP3、CASP8和CASP9表达^[5]。MK-4827（5μM）联合放疗（4Gy）处理食管鳞癌KYSE-30和KYSE-150细胞24小时，MK-4827显著增强放疗诱导的DNA双链断裂损伤（γ-H2AX表达升高），并促进细胞凋亡，同时通过抑制FANCG表达增强放疗敏感性^[6]。

在体内，在卵巢癌腹膜转移模型中，MK-4827（50mg/kg）灌胃处理荷瘤（ID8细胞或患者来源异种移植）小鼠（从接种后第3天或第6天开始，每周三次，持续3-8周），MK-4827显著抑制肿瘤生长、减少腹腔病灶数量及腹水体积，并诱导肿瘤细胞铁死亡^[7]。在动脉粥样硬化模型中，MK-4827（10mg/kg）灌胃处理高脂饮食喂养的ApoE⁻/⁻或Ldlr⁻/⁻小鼠（从饮食干预第4周或第16周开始，每周三次，持续8-12周），MK-4827显著减轻动脉粥样斑块负荷、缩小坏死核心面积、增加纤维帽厚度，并抑制平滑肌细胞表型转换^[8]。