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| Targets |
The primary target of Wee1 Inhibitor I is Wee1-like protein kinase (Wee1; also known as Wee1A kinase or WEE1hu). Wee1 is a tyrosine kinase that phosphorylates and inactivates CDC2/Cyclin B, thereby regulating the G2/M cell cycle checkpoint. The compound inhibits Wee1 with an IC₅₀ of 11 nM (0.011 μM). Wee1 Inhibitor I displays approximately 40-fold selectivity over the related checkpoint kinase Chk1 (IC₅₀ = 440 nM). By inhibiting Wee1, the compound promotes premature mitotic entry in cells with DNA damage, leading to mitotic catastrophe and cell death. This mechanism makes Wee1 inhibitors promising agents for combination with DNA-damaging chemotherapy or radiotherapy.
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| ln Vitro |
In vitro, Wee1 Inhibitor I demonstrates potent inhibition of Wee1 kinase activity with an IC₅₀ of 11 nM. The compound functions in an ATP-competitive manner, binding to the ATP-binding site of Wee1. It displays approximately 40-fold selectivity over Chk1 (IC₅₀ = 440 nM). The compound's ability to inhibit Wee1 can be evaluated in kinase activity assays using recombinant Wee1 protein and appropriate substrates. In cell-based assays, Wee1 Inhibitor I can promote premature mitotic entry and sensitize cancer cells to DNA-damaging agents. These in vitro activities demonstrate the compound's potential as a chemosensitizing agent.
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| ln Vivo |
In vivo, Wee1 Inhibitor I has been evaluated in preclinical models of cancer. By inhibiting Wee1, the compound promotes mitotic catastrophe in cancer cells with DNA damage, enhancing the efficacy of DNA-damaging chemotherapy or radiotherapy. The compound's selectivity for Wee1 over Chk1 may contribute to a favorable therapeutic index. In xenograft mouse models, Wee1 inhibitors have demonstrated antitumor activity when used as single agents or in combination with DNA-damaging agents. Further in vivo studies are needed to fully characterize the efficacy and safety of Wee1 Inhibitor I in various cancer models.
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| Enzyme Assay |
In vitro enzyme/receptor binding studies for Wee1 Inhibitor I focus on its kinase inhibition activity. Wee1 kinase activity can be measured using radiometric or fluorescence-based assays with appropriate substrates (e.g., peptide substrates or full-length CDC2). IC₅₀ values are determined from dose-response curves. Selectivity profiling against other kinases (e.g., Chk1, other checkpoint kinases, and related kinases) is performed using kinase panel screening. ATP-competitive nature of inhibition can be confirmed by kinetic analysis at varying ATP concentrations. These methods are for research purposes only.
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| Cell Assay |
In vitro cell-based assays for Wee1 Inhibitor I evaluate its effects on cell cycle progression and chemosensitization. Cancer cell lines are treated with Wee1 Inhibitor I at various concentrations (typically 0.1 nM to 10 µM) for 24-72 hours. Cell cycle analysis is performed using propidium iodide staining and flow cytometry. Phosphorylation of CDC2 (Tyr15) is measured by Western blot to assess Wee1 inhibition. Cell viability is assessed using MTT or CellTiter-Glo assays. Combination studies with DNA-damaging agents (e.g., cisplatin, gemcitabine, radiation) are performed to evaluate synergistic effects. Standard cell culture conditions are used with appropriate media and supplementation.
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| Animal Protocol |
In vivo animal studies for Wee1 Inhibitor I utilize xenograft mouse models bearing human tumor cell lines. Tumor-bearing mice are treated with Wee1 Inhibitor I via oral or intraperitoneal administration at various doses and schedules. Combination studies with DNA-damaging agents (e.g., cisplatin, gemcitabine) or radiation are conducted to evaluate synergistic antitumor efficacy. Tumor volumes are measured regularly using calipers, and body weight is monitored for toxicity assessment. Pharmacodynamic studies evaluate CDC2 phosphorylation, cell cycle markers, and apoptosis in tumor tissues. All procedures must comply with institutional animal care guidelines.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of Wee1 Inhibitor I are not fully characterized in publicly available literature. The compound has a molecular weight of 362.77 g/mol. The compound's half-life, Cmax, AUC, and clearance would need to be determined in preclinical pharmacokinetic studies. The compound is for research use only and is not approved for clinical use. Further studies are needed to fully characterize its pharmacokinetic properties.
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| Toxicity/Toxicokinetics |
The toxicity profile of Wee1 Inhibitor I is not fully characterized in publicly available literature. The compound is classified for research use only and not for human consumption. Standard safety precautions for handling kinase inhibitors apply, including the use of personal protective equipment and working in a chemical fume hood. Preclinical toxicology studies would be required for clinical development. The compound should be handled with care due to its potent biological activity.
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| References | |
| Additional Infomation |
Wee1 inhibitors refer to any drugs that can inhibit Wee1-like protein kinases (Wee1; Wee1A kinase; WEE1hu).
Additional information: Wee1 Inhibitor I has the CAS number 622855-37-2 and the molecular formula C₂₀H₁₁ClN₂O₃. The compound is also known as WEE1-IN-4. It is a potent, ATP-binding site-targeting inhibitor of Wee1 with an IC₅₀ of 11 nM (0.011 μM). The compound displays approximately 40-fold selectivity over Chk1 (IC₅₀ = 440 nM). Wee1 Inhibitor I functions in an ATP-competitive manner. Wee1 is a key regulator of the G2/M cell cycle checkpoint, and its inhibition sensitizes cancer cells to DNA-damaging agents. This product is for research use only and is not approved for clinical or therapeutic applications. |
| Molecular Formula |
C20H11N2O3CL
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| Molecular Weight |
362.76594
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| Exact Mass |
362.046
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| CAS # |
622855-37-2
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| PubChem CID |
10384072
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| Appearance |
Yellow to orange solid powder
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| LogP |
4.241
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
26
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| Complexity |
614
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
DPEXRCOBPACFOO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H11ClN2O3/c21-13-4-2-1-3-10(13)11-8-15-16(18-17(11)19(25)23-20(18)26)12-7-9(24)5-6-14(12)22-15/h1-8,22,24H,(H,23,25,26)
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| Chemical Name |
4-(2-chlorophenyl)-9-hydroxy-6H-pyrrolo[3,4-c]carbazole-1,3-dione
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~275.66 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.89 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.89 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7566 mL | 13.7828 mL | 27.5657 mL | |
| 5 mM | 0.5513 mL | 2.7566 mL | 5.5131 mL | |
| 10 mM | 0.2757 mL | 1.3783 mL | 2.7566 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05368506 | Withdrawn | Drug: Wee1 Inhibitor ZN-c3 | Advanced Fallopian Tube Carcinoma Advanced Ovarian Carcinoma Advanced Primary Peritoneal Carcinoma Anatomic Stage IV Breast Cancer AJCC v8 |
OHSU Knight Cancer Institute | 2023-07-30 | Early Phase 1 |
| NCT02791919 | Withdrawn | Drug: Cytarabine Biological: Filgrastim Drug: Fludarabine Phosphate |
CNS 2a CNS 2b CNS 2c CNS1 |
National Cancer Institute (NCI) | 2017-05-25 | Phase 1 |
| NCT02196168 | Terminated | Drug: Cisplatin Other: Laboratory Biomarker Analysis Other: Pharmacological Study |
Recurrent Hypopharyngeal Squamous Cell Carcinoma
Recurrent Laryngeal Squamous Cell Carcinoma Recurrent Laryngeal Verrucous Carcinoma Recurrent Lip and Oral Cavity Squamous Cell Carcinoma |
National Cancer Institute (NCI) | 2014-03 | Phase 2 |
| NCT02101775 | Active, not recruiting | Drug: Adavosertib Drug: Gemcitabine Hydrochloride Other: Laboratory Biomarker Analysis |
Ovarian Brenner Tumor Ovarian Carcinosarcoma Ovarian Clear Cell Cystadenocarcinoma Ovarian Endometrioid Adenocarcinoma |
National Cancer Institute (NCI) | 2014-07-21 | Phase 2 |
| NCT02381548 | Terminated | Drug: Adavosertib Drug: Belinostat Other: Laboratory Biomarker Analysis Other: Pharmacological Study |
Acute Myeloid Leukemia Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Myelodysplastic Syndrome Previously Treated Myelodysplastic Syndrome |
National Cancer Institute (NCI) | 2015-08-18 | Phase 1 |
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