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| Targets |
CDK12-IN-2 targets cyclin-dependent kinase 12 (CDK12), a kinase that regulates transcription elongation and RNA processing by phosphorylating Ser2 of the C-terminal domain (CTD) of RNA polymerase II. CDK12 also plays a critical role in the expression of genes involved in DNA damage response and homologous recombination repair. CDK12-IN-2 is a potent inhibitor with an IC50 of 52 nM for CDK12. It also inhibits CDK13, the closest homologue of CDK12, and shows selectivity over CDK2 (>100 μM), CDK7 (>10 μM), and CDK9 (16 μM). By inhibiting CDK12, the compound suppresses transcription of DNA repair genes and induces synthetic lethality in cancer cells with homologous recombination defects.
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| ln Vitro |
At low submicromolar concentrations, CDK12-IN-2 suppresses the phosphorylation of CTD Ser2 in SK-BR-3 cells. With an IC50 of 185 nM, it suppresses the phosphorylation of C-rest domain ser2. With an IC50 of 0.8 μM, CDK12-IN-2 inhibits the proliferation of BR-3 cells in comparison to SK-CDK12-IN-2 [1]. With respect to CDK12 inhibition, CDK12-IN-2 has a temporal inhibitory effect. Its IC50 values are 0.0078 μM, 0.042 μM, 0.057 μM, and 0.059 μM, or 0h, 1h, 2h, and 5h, respectively [1].
CDK12-IN-2 is a potent and selective nanomolar CDK12 inhibitor with an IC50 of 52 nM. It is also a strong CDK13 inhibitor. The compound exhibits excellent kinase selectivity over CDK2, 9, 8, and 7. CDK12-IN-2 inhibits C-terminal Ser2 phosphorylation of RNA polymerase II. It can be used as a chemical probe for the study of CDK12 function in transcription regulation, DNA repair pathways, and synthetic lethality approaches. |
| ln Vivo |
In vivo, CDK12-IN-2 is expected to have antitumor activity by inhibiting CDK12-mediated transcription of DNA repair genes, leading to impaired homologous recombination repair and increased sensitivity to DNA-damaging agents. The compound may induce synthetic lethality in cancer cells with pre-existing defects in DNA repair pathways. However, detailed in vivo efficacy data for CDK12-IN-2 are limited as it is primarily a research tool for in vitro studies. The compound is widely used in cancer research to study transcriptional regulation and DNA repair pathways.
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| Enzyme Assay |
Kinase inhibition assays for CDK12-IN-2 are performed using recombinant CDK12/Cyclin K enzyme complex and appropriate peptide substrates. The assay typically employs a fluorescence-based or radiometric format to measure kinase activity. CDK12-IN-2 is incubated with the enzyme, substrate, and ATP (at Km concentration) in assay buffer for 30-60 minutes. The reaction is stopped and product formation is quantified. IC50 values are calculated from concentration-response curves. Selectivity is assessed by screening CDK12-IN-2 against a panel of related kinases including CDK2, CDK7, CDK8, CDK9, and CDK13.
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| Cell Assay |
Cellular assays for CDK12 inhibition typically employ cancer cell lines. Cells are treated with varying concentrations of CDK12-IN-2 for 24-72 hours. Cell viability is assessed using MTT or CellTiter-Glo assays. RNA polymerase II CTD Ser2 phosphorylation is assessed by Western blot using phospho-specific antibodies (anti-RNA Pol II Ser2P). Gene expression changes are analyzed by qPCR or RNA-seq, focusing on CDK12 target genes involved in DNA repair (e.g., BRCA1, FANCI, ATM). DNA damage is assessed by measuring γ-H2AX foci formation. Cell cycle analysis is performed by propidium iodide staining.
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| Animal Protocol |
In vivo efficacy studies with CDK12-IN-2 would typically involve administration to tumor-bearing mice (oral or intraperitoneal). Tumor growth inhibition is assessed in xenograft models. Pharmacodynamic markers such as RNA Pol II Ser2 phosphorylation and expression of CDK12 target genes are measured in tumor tissues. However, detailed published in vivo protocols for CDK12-IN-2 are limited as the compound is primarily a research tool for in vitro studies. Standard protocols for kinase inhibitor evaluation in animal models would apply.
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| ADME/Pharmacokinetics |
CDK12-IN-2 has molecular weight 532.6 g/mol and molecular formula C28H29ClN8O? (exact formula may vary). The compound has good physicochemical properties supporting its use as a chemical probe. It is soluble in DMSO and should be stored at -20°C for long-term stability. The compound is typically used at concentrations of 0.1-10 μM in cellular assays. For in vivo studies, appropriate formulations would be required.
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| Toxicity/Toxicokinetics |
Toxicological data for CDK12-IN-2 are limited as it is a research compound. As a kinase inhibitor targeting transcription regulation, potential toxicities may include effects on normal cell proliferation and gene expression. The compound should be handled with appropriate laboratory safety precautions. In cell culture, CDK12-IN-2 is typically used at concentrations up to 10 μM, which are generally well-tolerated in short-term experiments. Standard preclinical safety assessments would be required for any therapeutic development.
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| References | |
| Additional Infomation |
CDK12-IN-2 is a potent, selective, and nanomolar CDK12 inhibitor with good physicochemical properties. It is also a strong CDK13 inhibitor. The compound exhibits excellent kinase selectivity over CDK2, 9, 8, and 7. CDK12-IN-2 is widely used in cancer research to study transcriptional regulation, DNA repair pathways, and synthetic lethality approaches. It provides a valuable chemical probe for oncology and therapeutic target validation studies.
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| Molecular Formula |
C32H32N6O2
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| Molecular Weight |
532.635486602783
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| Exact Mass |
532.258
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| CAS # |
2244987-03-7
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| PubChem CID |
134813906
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| Appearance |
White to off-white solid powder
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| LogP |
4.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
40
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| Complexity |
979
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(NCC1C=CC=CC=1)N(C1C=CC(C2C=CC(N(C)C=2)=O)=CC=1)C1CCC(CC1)NC1C=CC(C#N)=CN=1
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| InChi Key |
HDJBGURZVALLMD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H32N6O2/c1-37-22-26(10-18-31(37)39)25-8-13-28(14-9-25)38(32(40)35-20-23-5-3-2-4-6-23)29-15-11-27(12-16-29)36-30-17-7-24(19-33)21-34-30/h2-10,13-14,17-18,21-22,27,29H,11-12,15-16,20H2,1H3,(H,34,36)(H,35,40)
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| Chemical Name |
3-benzyl-1-[4-[(5-cyanopyridin-2-yl)amino]cyclohexyl]-1-[4-(1-methyl-6-oxopyridin-3-yl)phenyl]urea
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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 (~93.87 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.69 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (4.69 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8774 mL | 9.3872 mL | 18.7744 mL | |
| 5 mM | 0.3755 mL | 1.8774 mL | 3.7549 mL | |
| 10 mM | 0.1877 mL | 0.9387 mL | 1.8774 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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