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| Targets |
CDK12-IN-E9 targets cyclin-dependent kinase 12 (CDK12), which plays a critical role in transcription and DNA repair. As a covalent inhibitor, it forms an irreversible bond with CDK12, leading to sustained inhibition. It also inhibits CDK9 non-covalently. The compound has weak binding to CDK7/CyclinH (IC50 > 1 μM), suggesting selectivity for CDK12 and CDK9.
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| ln Vitro |
The treatment with CDK12-IN-E9 (E9; 10 nM-10 μM; 72 hours; Kelly, LAN5, SK-N-BE2, PC-9, NCI-H82, and NCI-H3122 cells) demonstrated effective lung anti-proliferative activity against cancer cells and THZ1R NB, with IC50 values ranging from 8 to 40 nM[1]. In THZ1r NB and lung cancer models, CDK12-IN-E9 (E9; 0-3000 nM; 6 hr; Kelly, PC-9, and NCI-H82 cells) therapy causes a dose-dependent reduction of phosphorylated and total RNAPII concurrent with MYC as well as lower expression of MCL1 [1]. CDK12-IN-E9 also resulted in higher PARP cleavage and subGI population in THZ1r lung cancer cells, however in NB cells, greater G2/M arrest was found after 24 h of exposure to CDK12-IN-E9. E9[1].
In vitro, CDK12-IN-E9 is a potent and selective covalent inhibitor of CDK12. It also inhibits CDK9 non-covalently. Its weak binding to CDK7/CyclinH (IC50 > 1 μM) suggests good selectivity over CDK7. The compound avoids ABC transporter-mediated efflux, which may enhance its intracellular accumulation. |
| ln Vivo |
CDK12-IN-E9 has shown promise in preclinical studies, particularly for tumors with deficiencies in DNA repair mechanisms, such as certain breast and ovarian cancers. As a potent CDK12 inhibitor with anticancer and antitumor activity, it is being investigated for the treatment of cancer. Further studies are needed to fully characterize its in vivo efficacy.
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| Enzyme Assay |
CDK12-IN-E9's activity as a CDK12 inhibitor is assessed using in vitro kinase assays to measure its ability to inhibit CDK12 enzymatic activity. As a covalent inhibitor, the compound's mechanism of action involves irreversible binding to CDK12, which can be evaluated using activity-based probes or washout experiments. Its selectivity for CDK12 over other kinases is assessed.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: Kelly, LAN5, SK-N-BE2, PC-9, NCI-H82, and NCI-H3122 Cell Tested Concentrations: 10 nM-10 μM Incubation Duration: 72 hrs (hours) Experimental Results: In cells shown Potent antiproliferative activity of THZ1R in NB and lung cancer cells with IC50 values ranging from 8 to 40 nM. Western Blot Analysis[1] Cell Types: Kelly, PC-9 and NCI-H82 Cell Tested Concentrations: 0 nM, 30 nM, 100 nM, 300 nM, 1000 nM, 3000 nM Incubation Duration: 6 hrs (hours) Experimental Results: Resulting doses of THZ1r NB and Phosphorylation- and total RNAPII-dependent reduction in lung cancer models. Cellular assays for CDK12-IN-E9 involve treating cancer cell lines with the compound and measuring its effects on cell proliferation, viability, and gene expression. The compound's ability to inhibit CDK12-mediated transcription and DNA repair pathways is assessed. Its effects on CDK9 activity are also evaluated. |
| Animal Protocol |
In vivo animal model protocols for CDK12-IN-E9 would involve its administration to tumor-bearing mice, particularly models of breast and ovarian cancer. The compound's antitumor efficacy, effects on DNA repair pathways, and pharmacokinetic properties would be assessed. Studies would evaluate its potential as a therapeutic agent for tumors with DNA repair deficiencies.
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| ADME/Pharmacokinetics |
CDK12-IN-E9 has a molecular weight of 434.53 and a molecular formula of C24H30N6O2. Specific pharmacokinetic data is not extensively detailed in the available literature. The compound's ability to avoid ABC transporter-mediated efflux suggests it may have favorable intracellular accumulation properties.
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| Toxicity/Toxicokinetics |
The toxicological profile of CDK12-IN-E9 has not been extensively characterized. As a research compound, it is intended for research use only and not for human consumption. Standard safety assessments would be required for clinical development.
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| References | |
| Additional Infomation |
CDK12-IN-E9 (CAS# 2020052-55-3) is a research compound used to study the role of CDK12 in transcription and DNA repair. It is a potent and selective covalent CDK12 inhibitor that also inhibits CDK9 non-covalently. It has shown promise in preclinical studies for tumors with DNA repair deficiencies. It is not approved for clinical use and is supplied as a research chemical.
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| Molecular Formula |
C24H30N6O2
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| Molecular Weight |
434.534004688263
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| Exact Mass |
434.243
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| CAS # |
2020052-55-3
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| PubChem CID |
122596923
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| Appearance |
White to off-white solid powder
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| LogP |
3.8
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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 |
8
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| Heavy Atom Count |
32
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| Complexity |
634
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| Defined Atom Stereocenter Count |
1
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| SMILES |
OCC[C@@H]1CCCCN1C1C=C(NC2C=CC=C(C=2)NC(C=C)=O)N2C(=C(C=N2)CC)N=1
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| InChi Key |
CDCHESFKYUNJPV-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C24H30N6O2/c1-3-17-16-25-30-22(26-18-8-7-9-19(14-18)27-23(32)4-2)15-21(28-24(17)30)29-12-6-5-10-20(29)11-13-31/h4,7-9,14-16,20,26,31H,2-3,5-6,10-13H2,1H3,(H,27,32)/t20-/m0/s1
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| Chemical Name |
N-[3-[[3-ethyl-5-[(2S)-2-(2-hydroxyethyl)piperidin-1-yl]pyrazolo[1,5-a]pyrimidin-7-yl]amino]phenyl]prop-2-enamide
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| Synonyms |
CDK12 IN E9; CDK12INE9; CDK12-IN-E9
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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 : ~125 mg/mL (~287.67 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 20.83 mg/mL (47.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 clear DMSO stock solution of 208.3 mg/mL to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.79 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 20.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3013 mL | 11.5067 mL | 23.0134 mL | |
| 5 mM | 0.4603 mL | 2.3013 mL | 4.6027 mL | |
| 10 mM | 0.2301 mL | 1.1507 mL | 2.3013 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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