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| Targets |
LY-3143921 targets Cdc7 kinase, a serine/threonine protein kinase that plays a critical role in the initiation of DNA replication. Cdc7 forms a complex with its regulatory subunit DBF4 (also known as ASK) and phosphorylates the minichromosome maintenance (MCM) complex, which is essential for the unwinding of DNA at replication origins. By inhibiting Cdc7 kinase activity, LY-3143921 prevents the initiation of DNA replication, leading to cell cycle arrest and potentially inducing senescence or apoptosis in cancer cells.
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| ln Vitro |
In Hep3B cells, LY3177833 (10 μM; 4 days) raises the SA-β-gal level [2].
In vitro, LY-3143921 is a potent inhibitor of Cdc7 kinase. It inhibits CDC7/DBF4 I with an IC50 of 3.3 nM and inhibits the phosphorylation of MCM2 at serine 53 (pMCM2 S53) with an IC50 of 290 nM. It is described as an ATP-competitive inhibitor with potential antineoplastic activity. The compound has shown broad in vitro anticancer activity across various cancer cell lines. Its selective inhibition of Cdc7 over other kinases makes it a valuable tool for studying the role of this kinase in cancer biology. |
| ln Vivo |
LY3177833 (Example 4; 10.4-31.2 mg/kg; oral gavage; twice daily; for 2 weeks; female athymic Balb/c nude mice with SW620 cells) therapy caused considerable tumor shrinkage in a dose-dependent manner . In addition, no substantial tumor growth was found within 2 weeks after drug cessation [1].
In vivo, LY-3143921 has demonstrated antitumor activity in preclinical models. As an orally active compound, it is suitable for convenient administration in animal studies. Its ability to inhibit cell-cycle progression may lead to anti-tumor activity. Specific in vivo efficacy data, including dosing regimens and tumor models, would be detailed in the primary literature. Its potential for treating various cancers is being investigated. |
| Enzyme Assay |
The inhibitory activity of LY-3143921 is assessed using in vitro kinase assays. Recombinant Cdc7/DBF4 kinase is incubated with a peptide substrate (e.g., MCM2-derived peptide) and varying concentrations of the compound in the presence of ATP. The transfer of phosphate to the substrate is quantified, and the IC50 is calculated from the dose-response curve. The compound's ATP-competitive nature can be confirmed by varying the ATP concentration in the assay.
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| Cell Assay |
Western Blot Analysis[2]
Cell Types: Hep3B Cell Tested Concentrations: 10 μM Incubation Duration: 4 days Experimental Results: Increased expression of human SA-β-gal. The cellular activity of LY-3143921 is evaluated in various cancer cell lines. Cells are treated with varying concentrations of the compound, and its effect on cell viability and proliferation is assessed using standard assays like MTT or CellTiter-Glo. Its ability to inhibit Cdc7 kinase activity in cells is confirmed by measuring the phosphorylation of MCM2 at serine 53 (pMCM2) by Western blot. The induction of senescence or apoptosis can also be assessed. |
| Animal Protocol |
Animal/Disease Models: Female athymic Balb/c nude mice (5-6 weeks old) SW620 cells [1]
Doses: 10.4 mg/kg, 20.8 mg/kg and 31.2 mg/kg Route of Administration: po (oral gavage); twice a day , lasted 2 weeks Experimental Results: Demonstrated dose-dependent anti-tumor activity in SW620 mouse xenograft tumor model. In animal studies, LY-3143921 is typically administered orally to mice bearing subcutaneous xenografts of human cancer cell lines. Dosing regimens are determined based on its pharmacokinetic properties. Tumor growth inhibition is measured, and at study termination, tumors are harvested for pharmacodynamic analysis, including assessment of pMCM2 levels and markers of cell cycle arrest or apoptosis. |
| ADME/Pharmacokinetics |
LY-3143921 is a small molecule with a molecular weight of 327.32 g/mol and a chemical formula of C16H14FN5O2. It is soluble in DMSO (10 mM) and is typically stored as a powder at -20°C. It is orally available, indicating favorable bioavailability for in vivo studies. Detailed pharmacokinetic parameters, such as half-life and volume of distribution, are available from preclinical studies.
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| Toxicity/Toxicokinetics |
Formal toxicology data for LY-3143921 is not extensively documented in the provided sources, as it is a research compound not intended for human therapeutic use. Its safety profile has not been established in comprehensive toxicology studies. However, its use in preclinical models at efficacious doses suggests it is tolerated in those contexts. As with all research chemicals, standard laboratory safety precautions should be followed.
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| References |
[1]. Robert Dean Dally, et al. CDC7 Inhibitors. Patent WO2014143601A1.
[2]. Li X, et al. First-generation species-selective chemical probes for fluorescence imaging of human senescence-associated β-galactosidase. Chem Sci. 2020 Jun 17;11(28):7292-7301. |
| Additional Infomation |
LY-3143921 (CAS: 1627696-53-0) is a potent and selective Cdc7 kinase inhibitor that serves as a valuable research tool for studying DNA replication and cell cycle regulation. Its IC50 of 3.3 nM against CDC7/DBF4 I makes it a highly potent compound for investigating the role of Cdc7 in cancer and for validating it as a therapeutic target. It has been cited in scientific literature, including clinical trial abstracts (J Clin Oncol 37, 2019), for its potential antineoplastic activity. It is available from various commercial suppliers for research purposes.
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| Molecular Formula |
C16H14FN5O2
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| Molecular Weight |
327.313066005707
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| Exact Mass |
327.113
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| CAS # |
1627696-53-0
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| Related CAS # |
LY3177833;1627696-51-8
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| PubChem CID |
156588327
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
24
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| Complexity |
477
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C[C@@]1(C2=C(C=C(C=C2)C3=CNN=C3)C(=O)N1)C4=NC=NC=C4F.O
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| InChi Key |
WSICFXBHDWUFRU-PKLMIRHRSA-N
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| InChi Code |
InChI=1S/C16H12FN5O.H2O/c1-16(14-13(17)7-18-8-19-14)12-3-2-9(10-5-20-21-6-10)4-11(12)15(23)22-16;/h2-8H,1H3,(H,20,21)(H,22,23);1H2/t16-;/m1./s1
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| Chemical Name |
(3R)-3-(5-fluoropyrimidin-4-yl)-3-methyl-6-(1H-pyrazol-4-yl)-2H-isoindol-1-one;hydrate
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0552 mL | 15.2760 mL | 30.5521 mL | |
| 5 mM | 0.6110 mL | 3.0552 mL | 6.1104 mL | |
| 10 mM | 0.3055 mL | 1.5276 mL | 3.0552 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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