MK-1775
(Synonyms: MK1775,MK 1775) 目录号 : GC16030
A Wee1 inhibitor and G2 checkpoint abrogator
Cas No.:955365-80-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
H1299 cells |
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Preparation Method |
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 |
200 nM, 1 h |
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Applications |
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. |
| Animal experiment [2]: | |
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Animal models |
6-week-old female nu/nu athymic mice |
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Preparation Method |
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 |
30 mg/kg. p.o., |
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Applications |
Single agent MK-1775 treatment produced greater than 50% inhibition of tumor growth in two xenografts (PANC286 and PANC198). |
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References: [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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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].
References:
[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]。
| Cas No. | 955365-80-7 | SDF | |
| 别名 | MK1775,MK 1775 | ||
| 化学名 | 1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-6-[4-(4-methylpiperazin-1-yl)anilino]-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-3-one | ||
| Canonical SMILES | CC(C)(C1=NC(=CC=C1)N2C3=NC(=NC=C3C(=O)N2CC=C)NC4=CC=C(C=C4)N5CCN(CC5)C)O | ||
| 分子式 | C27H32N8O2 | 分子量 | 500.6 |
| 溶解度 | ≥ 25.03mg/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 | 1.9976 mL | 9.988 mL | 19.976 mL |
| 5 mM | 0.3995 mL | 1.9976 mL | 3.9952 mL |
| 10 mM | 0.1998 mL | 0.9988 mL | 1.9976 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 | ||||||||||
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2.
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WEE1 kinase inhibitor MK-1775 sensitizes oral tongue squamous cell carcinoma cells to radiation irrespective of TP53 status
Objective: Oral tongue squamous cell carcinoma (OTSCC) frequently harbors non-functional p53 and depends on G2/M checkpoint mediated by WEE1. WEE1 suppression has been identified as a promising anti-tumor strategy. This study investigated the capacity of WEE1 kinase inhibitor (MK-1775) and its underlying mechanisms in enhancing radiation responses of OTSCC cells in vitro. Materials and methods: WEE1 kinase expression and its downstream target (CDK1) were investigated in OTSCC versus normal oral tissue. A synergistic combination of MK-1775 with radiation on OTSCC cell lines with different p53 statuses was assessed by viability assay. The radio-sensitizing effects of MK-1775 on apoptosis, cell cycle, DNA damage, and mitotic entry were also determined. Results: Irradiation enhanced CDK1 expression in all tested cell lines, though the effect was far more pronounced in p53 mutated cell lines. MK-1775 exhibited inhibitory effects against the survival of all cell lines and enhanced their response to the radiation. These effects were strongly elicited by induction of apoptosis and lethal mitosis, but less likely by abrogation of radiation-induced G2 arrest. Conclusion: These results demonstrate the efficacy of MK-1775 in enhancing the radiation effect on OTSCC in vitro associated with a significant apoptotic death rate, identifying WEE1 inhibitor as a potent radiosensitizer in OTSCC irrespective of p53 mutational status.
WEE1 Inhibitor: Clinical Development
Purpose of review: WEE1 inhibitor has been shown to potential chemotherapy or radiotherapy sensitivity in preclinical models, particularly in p53-mutated or deficient cancer cells although not exclusively. Here, we review the clinical development of WEE1 inhibitor in combination with chemotherapy or radiotherapy with concurrent chemotherapy as well as its combination with different novel agents.
Recent findings: Although several clinical trials have shown that WEE1 inhibitor can be safely combined with different chemotherapy agents as well as radiotherapy with concurrent chemotherapy, its clinical development has been hampered by the higher rate of grade 3 toxicities when added to standard treatments. A few clinical trials had also been conducted to test WEE1 inhibitor using TP53 mutation as a predictive biomarker. However, TP53 mutation has not been shown to be the most reliable predictive biomarker and the benefit of adding WEE1 inhibitor to chemotherapy has been modest, even in TP53 biomarker-driven studies. There are ongoing clinical trials testing WEE1 inhibitor with novel agents such as ATR and PAPR inhibitors as well as anti-PDL1 immunotherapy, which may better define the role of WEE1 inhibitor in the future if any of the novel treatment combination will show superior anti-tumor efficacy with a good safety profile compared to monotherapy and/or standard treatment.
WEE1 inhibition induces anti-tumor immunity by activating ERV and the dsRNA pathway
Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell-dependent manner. A WEE1 inhibition-induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.
A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target
The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer cells. This review recapitulates and discusses the most recent findings on the biological function of WEE1/PKMYT1 during the cell cycle and in the DNA damage repair, with a focus on their dual role as tumor suppressors in nonmalignant cells and pseudo-oncogenes in cancer cells. We here report the available data on the molecular and functional alterations of WEE1/PKMYT1 kinases in both hematological and solid tumors. Moreover, we summarize the preclinical information on 36 chemo/radiotherapy agents, and in particular their effect on cell cycle checkpoints and on the cellular WEE1/PKMYT1-dependent response. Finally, this review outlines the most important pre-clinical and clinical data available on the efficacy of WEE1/PKMYT1 inhibitors in monotherapy and in combination with chemo/radiotherapy agents or with other selective inhibitors currently used or under evaluation for the treatment of cancer patients.
MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells
Purpose: Radiotherapy is commonly used to treat a variety of solid tumors. However, improvements in the therapeutic ratio for several disease sites are sorely needed, leading us to assess molecularly targeted therapeutics as radiosensitizers. The aim of this study was to assess the wee1 kinase inhibitor, MK-1775, for its ability to radiosensitize human tumor cells.
Experimental design: Human tumor cells derived from lung, breast, and prostate cancers were tested for radiosensitization by MK-1775 using clonogenic survival assays. Both p53 wild-type and p53-defective lines were included. The ability of MK-1775 to abrogate the radiation-induced G? block, thereby allowing cells harboring DNA lesions to prematurely progress into mitosis, was determined using flow cytometry and detection of γ-H2AX foci. The in vivo efficacy of the combination of MK-1775 and radiation was assessed by tumor growth delay experiments using a human lung cancer cell line growing as a xenograft tumor in nude mice.
Results: Clonogenic survival analyses indicated that nanomolar concentrations of MK-1775 radiosensitized p53-defective human lung, breast, and prostate cancer cells but not similar lines with wild-type p53. Consistent with its ability to radiosensitize, MK-1775 abrogated the radiation-induced G? block in p53-defective cells but not in p53 wild-type lines. MK-1775 also significantly enhanced the antitumor efficacy of radiation in vivo as shown in tumor growth delay studies, again for p53-defective tumors.
Conclusions: These results indicate that p53-defective human tumor cells are significantly radiosensitized by the potent and selective wee1 kinase inhibitor, MK-1775, in both the in vitro and in vivo settings. Taken together, our findings strongly support the clinical evaluation of MK-1775 in combination with radiation.