Background
MK-1775 is a potent and selective small-molecule inhibitor of Wee1 kinase with an IC50 value of 5.2 nM. MK-1775 is 2- to 3-fold less potent against Yes with an IC50 of 14 nM.[1].
In vitro efficacy test it shown that MK-1775 inhibited phosphorylation of CDC2 at Tyr15 with an EC50 value of 85 nM in cells pretreated with gemcitabine. MK-1775 treatment induced pHH3 in a dose-dependent manner with an EC50 value of 81 nM.[1] In vitro efficacy test it indicated that treatment with 10 nM panobinostat in combination with 250 nM or 500 nM MK-1775 in U937 cells, the combination index (CI) values were 0.95 and 0.73, while U937 cells treated with 20 nM panobinostat in combination with 250 nM or 500 nM MK-1775 were 0.39 and 0.40, respectively.[3] In vitro, treatment with 0.1, 0.3, 1 μM of MK-1775 for 48 h in LSCC cells and TU212 and KB-3-1 cells dose-dependently induced early apoptosis (Annexin V+/PI-) and late apoptosis (Annexin V+/PI+) . Moreover, after MK-1775 treatment, the protein levels of apoptosis marker cleaved-PARP was increased in a dose-depend manner[5].
In vivo, treatment with 60 mg/kg MK-1775 orally enhances H1299 xenograft tumor response to fractionated radiotherapy in nude mice.[2] In vivo experiment it indicated that treatment with either MK-1775 (20 mg/kg) or panobinostat (10 mg/kg) alone in mice bearing BxPC-3 xenograft tumors had modest delay of externally measurable tumor growth (30.9% and 37.8% on day 20, respectively). However, combination the MK-1775 (20 mg/kg) with panobinostat (10 mg/kg) can marked delay the tumor growth with 58.7% tumor growth inhibition on day 20.[4] In vivo, Nude Mice were treated with 50 mg/kg orally MK-1775, MK-1775 inhibited the growth of KB-3-1 xenografts with the inhibition ratio of 30.04% by reducing the tumor volumes and weights. And MK-1775 also can cause toxicity in mice at the indicated dose.[6].
参考文献:
[1]Hirai H, et al. MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther. 2010 Apr 1;9(7):514-22.
[2]Bridges KA, et al. MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res. 2011 Sep 1;17(17):5638-48.
[3]Qi W, et al. Synergistic anti-leukemic interactions between panobinostat and MK-1775 in acute myeloid leukemia ex vivo. Cancer Biol Ther. 2015;16(12):1784-93.
[4]Wang G, et al. Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer. Cancer Lett. 2015 Jan 28;356(2 Pt B):656-68.
[5]Yuan ML, et al Inhibition of WEE1 Suppresses the Tumor Growth in Laryngeal Squamous Cell Carcinoma. Front Pharmacol. 2018 Sep 28;9:1041.
[6]Yuan ML, et al. Inhibition of WEE1 Suppresses the Tumor Growth in Laryngeal Squamous Cell Carcinoma. Front Pharmacol. 2018 Sep 28;9:1041.
MK-1775 是一种有效的选择性 Wee1 激酶小分子抑制剂，IC50 值为 5.2 nM。 MK-1775 对抗 Yes 的效力低 2 到 3 倍，IC50 为 14 nM。[1]。
体外药效测试表明，MK-1775 在吉西他滨预处理的细胞中抑制 Tyr15 位点 CDC2 的磷酸化，EC50 值为 85 nM。 MK-1775处理以剂量依赖性方式诱导pHH3，EC50值为81 nM。[1]体外药效试验表明，10 nM帕比司他联合250 nM或500 nM处理MK-1775 在 U937 细胞中的组合指数 (CI) 值分别为 0.95 和 0.73，而使用 20 nM 帕比司他联合 250 nM 或 500 nM MK-1775 处理的 U937 细胞分别为 0.39 和 0.40。[3 ] 在体外，用 0.1、0.3、1 μM MK-1775 处理 LSCC 细胞和 TU212 和 KB-3-1 细胞 48 小时，剂量依赖性地诱导早期细胞凋亡 (Annexin V+/PI-) 和晚期细胞凋亡细胞凋亡（膜联蛋白 V+/PI+）。此外，经MK-1775处理后，细胞凋亡标志物cleaved-PARP的蛋白水平呈剂量依赖性升高[5]。
在体内，口服 60 mg/kg MK-1775 可增强 H1299 异种移植肿瘤对裸鼠分割放疗的反应。[2] 体内实验表明，用 MK-1775 治疗(20 mg/kg) 或帕比司他 (10 mg/kg) 在携带 BxPC-3 异种移植肿瘤的小鼠中具有适度延迟的外部可测量肿瘤生长（第 20 天分别为 30.9% 和 37.8%）。然而，将 MK-1775 (20 mg/kg) 与帕比司他 (10 mg/kg) 联用可显着延缓肿瘤生长，第 20 天肿瘤生长抑制率为 58.7%。[4] 在体内，裸鼠口服50 mg/kg MK-1775，MK-1775通过减少肿瘤体积和重量抑制KB-3-1异种移植物的生长，抑制率为30.04%。并且 MK-1775 在指定剂量下也会对小鼠造成毒性。[6]。
Protocol
| Cell experiment [1]: |
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Cell lines
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H1299 cells
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Preparation Method
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H1299 cells were treated for 1 h with 200 nM MK-1775, irradiated with 7.5 Gy, incubated for an additional 18 h in MK-1775, and harvested for assessment of apoptosis at 24, 48, and 72 h post-irradiation.
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Reaction Conditions
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200 nM, 1 h
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Applications
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The dose of 7.5 Gy induced levels of apoptosis of only about 5% above control at any time point and these levels of apoptosis were not significantly enhanced by MK-1775.
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| Animal experiment [2]: |
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Animal models
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6-week-old female nu/nu athymic mice
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Preparation Method
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When tumors reached a volume of ~200 mm3, mice were individually identified and randomly assigned to treatment groups, with 5–6 mice (8–10 evaluable tumors) in each group: 1) control; 2) MK-1775 (30 mg/kg. p.o., once daily for 4 weeks; 3) GEM (100 mg/kg, i.p., twice weekly on days 1 and 4) for 4 weeks; 4) GEM followed 24 h later by MK-1775 in the above mentioned dose.
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Dosage form
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30 mg/kg. p.o.,
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Applications
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Single agent MK-1775 treatment produced greater than 50% inhibition of tumor growth in two xenografts (PANC286 and PANC198).
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参考文献:
[1]. Bridges KA, et al. MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res. 2011 Sep 1;17(17):5638-48.
[2]. Rajeshkumar NV, et al. MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res. 2011 May 1;17(9):2799-806.
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