Wee1 Inhibitor
目录号 : GC49430
An inhibitor of Wee1
Cas No.:622855-37-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >95.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Wee1 inhibitor is an inhibitor of the checkpoint kinase Wee1 (IC50 = 11 nM).1 It is selective for Wee1 over checkpoint kinase 1 (Chk1; IC50 = 440 nM). Wee1 inhibitor also inhibits the ATPase activity of LptB, an enzyme involved in the transport and assembly of LPS (IC50 = 25 µM for the E. coli enzyme).2
1.Palmer, B.D., Thompson, A.M., Booth, R.J., et al.4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitutionJ. Med. Chem.49(16)4896-4911(2006) 2.Gronenberg, L.S., and Kahne, D.Development of an activity assay for discovery of inhibitors of lipopolysaccharide transportJ. Am. Chem. Soc.132(8)2518-2519(2010)
| Cas No. | 622855-37-2 | SDF | |
| Canonical SMILES | OC1=CC=C(N([H])C2=C3C4=C(C(N([H])C4=O)=O)C(C5=C(Cl)C=CC=C5)=C2)C3=C1 | ||
| 分子式 | C20H11ClN2O3 | 分子量 | 362.8 |
| 溶解度 | DMSO: 10 mg/ml,Ethanol: 10 mg/ml | 储存条件 | -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 | 2.7563 mL | 13.7817 mL | 27.5634 mL |
| 5 mM | 0.5513 mL | 2.7563 mL | 5.5127 mL |
| 10 mM | 0.2756 mL | 1.3782 mL | 2.7563 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % 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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Wee1 Inhibitor: Clinical Development
Curr Oncol Rep 2021 Jul 16;23(9):107.PMID:34269904DOI:10.1007/s11912-021-01098-8.
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.
Targeting WEE1 Kinase in Cancer
Trends Pharmacol Sci 2016 Oct;37(10):872-881.PMID:27427153DOI:10.1016/j.tips.2016.06.006.
WEE1 kinase plays a crucial role in the G2-M cell-cycle checkpoint arrest for DNA repair before mitotic entry. Normal cells repair damaged DNA during G1 arrest; however, cancer cells often have a deficient G1-S checkpoint and depend on a functional G2-M checkpoint for DNA repair. WEE1 is expressed at high levels in various cancer types including breast cancers, leukemia, melanoma, and adult and pediatric brain tumors. Many of these cancers are treated with DNA-damaging agents; therefore, targeting WEE1 for inhibition and compromising the G2-M checkpoint presents an opportunity to potentiate therapy. In this review we summarize the current WEE1 inhibitors, the potential for further inhibitor development, and the challenges in the clinic for the Wee1 Inhibitor strategy.
Targeting MUS81 promotes the anticancer effect of Wee1 Inhibitor and immune checkpoint blocking combination therapy via activating cGAS/STING signaling in gastric cancer cells
J Exp Clin Cancer Res 2021 Oct 8;40(1):315.PMID:34625086DOI:10.1186/s13046-021-02120-4.
Background: Identification of genomic biomarkers to predict the anticancer effects of indicated drugs is considered a promising strategy for the development of precision medicine. DNA endonuclease MUS81 plays a pivotal role in various biological processes during malignant diseases, mainly in DNA damage repair and replication fork stability. Our previous study reported that MUS81 was highly expressed and linked to tumor metastasis in gastric cancer; however, its therapeutic value has not been fully elucidated. Methods: Bioinformatics analysis was used to define MUS81-related differential genes, which were further validated in clinical tissue samples. Gain or loss of function MUS81 cell models were constructed to elucidate the effect and mechanism of MUS81 on WEE1 expression. Moreover, the antitumor effect of targeting MUS81 combined with WEE1 inhibitors was verified using in vivo and in vitro assays. Thereafter, the cGAS/STING pathway was evaluated, and the therapeutic value of MUS81 for immunotherapy of gastric cancer was determined. Results: In this study, MUS81 negatively correlated with the expression of cell cycle checkpoint kinase WEE1. Furthermore, we identified that MUS81 regulated the ubiquitination of WEE1 via E-3 ligase β-TRCP in an enzymatic manner. In addition, MUS81 inhibition could sensitize the anticancer effect of the Wee1 Inhibitor MK1775 in gastric cancer in vitro and in vivo. Interestingly, when MUS81 was targeted, it increased the accumulation of cytosolic DNA induced by MK1775 treatment and activated the DNA sensor STING-mediated innate immunity in the gastric cancer cells. Thus, the Wee1 Inhibitor MK1775 specifically enhanced the anticancer effect of immune checkpoint blockade therapy in MUS81 deficient gastric cancer cells. Conclusions: Our data provide rational evidence that targeting MUS81 could elevate the expression of WEE1 by regulating its ubiquitination and could activate the innate immune response, thereby enhancing the anticancer efficacy of Wee1 Inhibitor and immune checkpoint blockade combination therapy in gastric cancer cells.
Discovery of ZN-c3, a Highly Potent and Selective Wee1 Inhibitor Undergoing Evaluation in Clinical Trials for the Treatment of Cancer
J Med Chem 2021 Sep 9;64(17):13004-13024.PMID:34423975DOI:10.1021/acs.jmedchem.1c01121.
Wee1 inhibition has received great attention in the past decade as a promising therapy for cancer treatment. Therefore, a potent and selective Wee1 Inhibitor is highly desirable. Our efforts to make safer and more efficacious Wee1 inhibitors led to the discovery of compound 16, a highly selective Wee1 Inhibitor with balanced potency, ADME, and pharmacokinetic properties. The chiral ethyl moiety of compound 16 provided an unexpected improvement of Wee1 potency. Compound 16, known as ZN-c3, showed excellent in vivo efficacy and is currently being evaluated in phase 2 clinical trials.
Phase II Study of the Wee1 Inhibitor Adavosertib in Recurrent Uterine Serous Carcinoma
J Clin Oncol 2021 May 10;39(14):1531-1539.PMID:33705205DOI:10.1200/JCO.20.03167.
Purpose: Uterine serous carcinoma (USC) is a distinct histologic subtype of endometrial cancer, with molecular characteristics suggesting frequent cell-cycle dysregulation paired with a high level of oncogene-driven replication stress. Adavosertib is a potent and selective oral inhibitor of the WEE1 kinase, a key regulator of the G2/M and S phase cell-cycle checkpoints. Because cells with impaired cell-cycle regulation and high replication stress may be vulnerable to WEE1 inhibition, we conducted this study to assess the activity of adavosertib monotherapy in women with recurrent USC. Patients and methods: This was a single-arm two-stage phase II study with coprimary end points of objective response rate (ORR) and rate of progression-free survival at 6 months (PFS6). Women with recurrent USC were treated with adavosertib monotherapy at a starting dose of 300 mg orally once daily days 1 through 5 and 8 through 12 of a 21-day cycle until disease progression. Results: In 34 evaluable patients, 10 total responses (one confirmed complete response, eight confirmed partial responses, and one unconfirmed partial response) were observed with adavosertib monotherapy, for an ORR of 29.4% (95% CI, 15.1 to 47.5). Sixteen patients were progression-free at 6 months, for a PFS6 rate of 47.1% (95% CI, 29.8 to 64.9). Median PFS was 6.1 months, and median duration of response was 9.0 months. Frequent treatment-related adverse events (AEs) included diarrhea (76.5%), fatigue (64.7%), nausea (61.8%), and hematologic AEs. No clear correlation of clinical activity with specific molecular alterations was observed in an exploratory biomarker analysis. Conclusion: Adavosertib monotherapy demonstrated encouraging and durable evidence of activity in women with USC, and further investigation of this agent in this cancer and biomarkers of activity are indicated.