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| Targets |
ZNL-02-096 targets Wee1 kinase for degradation via the proteasome. The compound is a PROTAC (PROteolysis TArgeting Chimera) that simultaneously binds to Wee1 (via the AZD1775 moiety) and to the E3 ubiquitin ligase cereblon (via the pomalidomide moiety). This brings Wee1 into proximity with cereblon, leading to ubiquitination of Wee1 and its subsequent degradation by the proteasome. ZNL-02-096 has CRBN-dependent pharmacology that is distinct from AZD1775, which justifies the further evaluation of selective Wee1 degraders. The compound's selectivity for Wee1 over PLK1 is a significant advantage over the parent Wee1 inhibitor AZD1775, which also inhibits PLK1.
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| ln Vitro |
Pomalidomide-C3-adavosertib (1 nM-10 μM; 24, 48, and 72 hours) is synergistic with olaparib and causes antiproliferative effects that are dependent on CRBN [1]. Pomalidomide-C3-adavosertib (100 nM; 24 h) causes apoptosis, disruption of the G2/M checkpoint, and damage to DNA [1]. In MOLT4 cells, Pomalidomide-C3-adavosertib (1 nM–10 μM; 6 hours) destroys Wee1[1].
In vitro, ZNL-02-096 (6 hours) degrades Wee1 in OVCAR8 cells, with maximal degradation observed at 100 nM treatment. ZNL-02-096 (100 nM, 24 hours) induces DNA damage, apoptosis, and G2/M checkpoint dysregulation. The compound shows antiproliferative effects in 300 cancer cell lines. ZNL-02-096 has an IC50 of 3.58 nM for Wee1 degradation. The compound's rapid and potent degradation of Wee1, combined with its selectivity over PLK1, makes it a valuable tool for studying the role of Wee1 in cancer and for developing new cancer therapies. |
| ln Vivo |
In vivo data for ZNL-02-096 is limited in the available literature. The compound is primarily used as a research tool for in vitro studies of Wee1 degradation and cancer cell biology. ZNL-02-096's ability to induce DNA damage, apoptosis, and G2/M checkpoint dysregulation suggests that it may have antitumor activity in vivo, but specific in vivo efficacy data has not been extensively reported.
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| Enzyme Assay |
ZNL-02-096's degradation of Wee1 is assessed using cellular degradation assays. Cells are treated with varying concentrations of ZNL-02-096 for various time points; Wee1 protein levels are assessed by Western blot; the DC50 (concentration for 50% degradation) and Dmax (maximum degradation) are calculated. Ubiquitination of Wee1 is assessed by immunoprecipitation followed by Western blot for ubiquitin. Selectivity for Wee1 over PLK1 is assessed by Western blot for PLK1 protein levels. These assays provide quantitative information on the potency and selectivity of ZNL-02-096 as a Wee1 degrader.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: OVCAR8, COV362 and Kuramochi Cell Tested Concentrations: 1 nM-10 μM Incubation Duration: 24, 48 and 72 hrs (hours) Experimental Results: Wee1 is degraded in OVCAR8 cells, with maximum degradation observed at 100 nM treatment. Cell cycle analysis [1] Cell Types: MOLT4 Cell Tested Concentrations: 100nM Incubation Duration: 24 hrs (hours) Experimental Results: Experimental Results: diminished pCDK1Y15, increased apoptosis, and increased unrepaired DNA. Western Blot Analysis[1] Cell Types: MOLT4 Cell Tested Concentrations: 1 nM-10 μM Incubation Duration: 6 hrs (hours) Experimental Results: Wee1 is degraded after 6 hrs (hours) of treatment in MOLT4 cells and induces downstream changes from Wee1 loss, including diminished phosphorylation cyclin-dependent kinase 1 (pCDK1) and pH 3 were elevated. ZNL-02-096 is tested on cultured cancer cells (e.g., OVCAR8, MOLT-4) to assess its effects on Wee1 degradation, cell proliferation, and apoptosis. Cells are treated with varying concentrations of ZNL-02-096; Wee1 protein levels are assessed by Western blot; cell proliferation is assessed by MTT or CellTiter-Glo assays; cell cycle analysis is performed by flow cytometry; DNA damage is assessed by measuring γH2AX levels by Western blot or immunofluorescence; apoptosis is assessed by Annexin V staining or caspase activity assays. These cell-based assays demonstrate the mechanism of action and antiproliferative activity of ZNL-02-096. |
| Animal Protocol |
Animal studies for ZNL-02-096 are limited in the available literature. The compound has not been extensively evaluated in vivo, and specific animal models, dosing regimens, and efficacy endpoints have not been reported. ZNL-02-096 is primarily used as a research tool for in vitro studies. Further studies are needed to characterize the in vivo activity and therapeutic potential of ZNL-02-096.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for ZNL-02-096 is not available in the literature. The compound is used primarily in research settings for in vitro studies. As a PROTAC molecule, ZNL-02-096 has a larger molecular weight (799.88 g/mol) than typical small molecule inhibitors, which may affect its oral bioavailability and pharmacokinetic properties.
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| Toxicity/Toxicokinetics |
Toxicological data for ZNL-02-096 is not available in the literature. The compound is used in research settings and has not been evaluated for clinical safety. As a Wee1 degrader, ZNL-02-096 may have effects on normal cells as well as cancer cells, and its toxicity profile would need to be characterized in future studies.
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| References | |
| Additional Infomation |
ZNL-02-096 is a potent and selective Wee1 degrader (PROTAC) with an IC50 of 3.58 nM. The compound comprises the Wee1 inhibitor AZD1775 linked to pomalidomide, a cereblon-binding ligand. ZNL-02-096 induces rapid and potent degradation of Wee1 while sparing PLK1, a secondary target of AZD1775. The compound induces DNA damage, apoptosis, and G2/M checkpoint dysregulation in cancer cells. ZNL-02-096 shows antiproliferative effects in 300 cancer cell lines. The compound represents a promising approach for targeting Wee1 in cancer therapy and is used as a research tool for studying the role of Wee1 in cancer cell biology. ZNL-02-096 is not approved as a therapeutic agent and is used for research purposes only.
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| Molecular Formula |
C42H45N11O6
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| Molecular Weight |
799.876807928085
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| Exact Mass |
799.355
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| CAS # |
2414418-49-6
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| PubChem CID |
153555373
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
14
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
59
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| Complexity |
1580
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(=O)C2=C(C(NCCCN3CCN(C4=CC=C(NC5=NC=C6C(=O)N(CC=C)N(C7=NC(C(O)(C)C)=CC=C7)C6=N5)C=C4)CC3)=CC=C2)C(=O)N1C1CCC(=O)NC1=O
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| InChi Key |
LZUDSNUROXNVPH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C42H45N11O6/c1-4-19-51-38(56)29-25-44-41(48-36(29)53(51)33-11-6-10-32(46-33)42(2,3)59)45-26-12-14-27(15-13-26)50-23-21-49(22-24-50)20-7-18-43-30-9-5-8-28-35(30)40(58)52(39(28)57)31-16-17-34(54)47-37(31)55/h4-6,8-15,25,31,43,59H,1,7,16-24H2,2-3H3,(H,44,45,48)(H,47,54,55)
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| Chemical Name |
2-(2,6-dioxopiperidin-3-yl)-4-[3-[4-[4-[[1-[6-(2-hydroxypropan-2-yl)pyridin-2-yl]-3-oxo-2-prop-2-enylpyrazolo[3,4-d]pyrimidin-6-yl]amino]phenyl]piperazin-1-yl]propylamino]isoindole-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: ~50 mg/mL (~62.5 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (1.56 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 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 DMSO stock solution (12.5 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2502 mL | 6.2509 mL | 12.5019 mL | |
| 5 mM | 0.2500 mL | 1.2502 mL | 2.5004 mL | |
| 10 mM | 0.1250 mL | 0.6251 mL | 1.2502 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.
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