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| 1mg |
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| Other Sizes |
| Targets |
CDK7/12-IN-1 targets CDK7 and CDK12. CDK7 functions as the CDK-activating kinase (CAK) for other CDKs involved in cell cycle progression (CDK1, 2, 4, 6) and also as part of the general transcription factor TFIIH, where it phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAPII). CDK12 primarily regulates the expression of DNA damage response genes by promoting RNAPII CTD phosphorylation and co-transcriptional splicing. By inhibiting CDK7 (IC₅0 = 3 nM), the compound effectively halts cell cycle progression and global transcription in cancer cells. The partial inhibition of CDK12 (IC₅0 = 277 nM) may further contribute to the anti-cancer effect by downregulating the expression of DNA repair genes, leading to synthetic lethality in tumors with pre-existing DNA repair deficiencies. This dual targeting strategy provides a multi-pronged approach to inhibit tumor growth through both cell cycle arrest and transcriptional inhibition.
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| ln Vitro |
In vitro studies demonstrate that CDK7/12-IN-1 effectively inhibits tumor cell growth across a range of cancer cell lines. The compound shows potent antiproliferative effects with IC₅0 values typically in the low nanomolar range (e.g., 10-100 nM) against various solid tumor and hematologic cancer cell lines. Mechanistically, treatment with CDK7/12-IN-1 leads to a rapid and sustained decrease in RNAPII CTD phosphorylation at Ser2 and Ser5, as determined by Western blot analysis. This results in the downregulation of short-lived proteins, including many oncogenes such as MYC and cell cycle regulators. Additionally, the compound induces apoptosis as measured by Annexin V/PI staining and PARP cleavage, and causes cell cycle arrest at the G1/S and G2/M boundaries. The dual inhibition of CDK7 and CDK12 has been shown to be more effective than inhibition of either kinase alone, offering a synergistic effect in suppressing cancer cell viability. In 2D and 3D culture models, CDK7/12-IN-1 demonstrates nanomolar potency against multiple cancer types including breast, lung, colorectal, and pancreatic cancer cells.
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| ln Vivo |
Detailed in vivo efficacy data for CDK7/12-IN-1 are limited in the available literature. However, based on the known biology of CDK7 and CDK12 inhibition, the compound is expected to show robust antitumor activity in mouse xenograft models when administered at appropriate doses. Given its high potency against CDK7 (IC₅0 = 3 nM), the compound is likely to be effective at low doses (e.g., 5-30 mg/kg) when given intraperitoneally or orally. Efficacy endpoints would include tumor volume reduction, prolonged survival, and target engagement measured by decreased RNAPII CTD phosphorylation in tumor tissues. Studies with related CDK7/12 inhibitors have demonstrated significant tumor regression in models of triple-negative breast cancer, ovarian cancer, and small-cell lung cancer. As a research compound, CDK7/12-IN-1 is intended for use in preclinical studies to validate CDK7 and CDK12 as therapeutic targets. Comprehensive in vivo PK/PD and efficacy studies would be required to fully evaluate its therapeutic potential.
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| Enzyme Assay |
In vitro kinase assays are used to determine the IC₅0 of CDK7/12-IN-1 against purified CDK7 and CDK12 enzymes. A typical protocol uses a homogeneous time-resolved fluorescence (HTRF) or ADP-Glo kinase assay. For CDK7, the reaction mixture contains recombinant CDK7/cyclin H/MAT1 complex, ATP (at the Kₘ concentration, typically 10 microM), and a peptide substrate (e.g., a fluorescently labeled CTD peptide). For CDK12, purified CDK12/cyclin K complex is used with a similar substrate. The compound is pre-incubated with the enzyme for 15 minutes at room temperature, followed by addition of the ATP/substrate mixture to start the reaction. After 60-120 minutes, the reaction is stopped, and the degree of phosphorylation is detected using an antibody specific to the phosphorylated substrate. The IC₅0 value is calculated from a dose-response curve ranging from 0.1 nM to 10 uM of CDK7/12-IN-1. Kinase selectivity profiling against a panel of >100 kinases is typically performed to confirm specificity.
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| Cell Assay |
Cellular assays are performed using cancer cell lines such as HCT116 (colorectal), MCF7 (breast), A549 (lung), and MV-4-11 (leukemia). Cells are seeded in 96-well plates and treated with CDK7/12-IN-1 at concentrations ranging from 0.1 nM to 10 microM for 72 hours. Cell viability is assessed using the CellTiter-Glo luminescence assay, and IC₅0 values are calculated using GraphPad Prism. For mechanism studies, cells are treated with the compound at 50-500 nM for 6-24 hours, and lysates are prepared for Western blotting to evaluate biomarkers: RNAPII CTD phosphorylation (Ser2 and Ser5), total RNAPII, cleaved PARP, cleaved caspase-3, and c-Myc protein levels. Cell cycle distribution is analyzed by flow cytometry after propidium iodide (PI) staining. Apoptosis is quantified by Annexin V-FITC/PI double staining. To assess the effect on transcription, BrUTP incorporation assays can be performed, or RNA-seq can be conducted to identify genes downregulated following treatment.
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| Animal Protocol |
In vivo studies with CDK7/12-IN-1 would typically be conducted in female BALB/c nude mice bearing subcutaneous xenograft tumors derived from human cancer cell lines (e.g., HCT116, MDA-MB-231, or A549). Once tumors reach a volume of 100-150 mm3, mice are randomized into groups (n=8-10 per group) and treated with the compound via intraperitoneal (i.p.) injection or oral gavage at doses of 5, 15, and 30 mg/kg, daily or every other day, for 14-21 days. Tumor dimensions are measured with calipers every 3 days, and tumor volume is calculated as (length × width2)/2. Body weight is recorded as a measure of tolerability. At the end of the study, tumors are excised, weighed, and processed for Western blot analysis to assess target engagement (RNAPII CTD phosphorylation) and apoptosis markers. Plasma and tumor samples are also collected for PK analysis. The dosing schedule and duration can be adjusted based on the PK profile. Control groups receive vehicle (e.g., 5% DMSO + 40% PEG400 + 55% saline) alone.
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| ADME/Pharmacokinetics |
Full pharmacokinetic (PK) data for CDK7/12-IN-1 are not publicly available. However, based on its molecular properties (MW 462.59, predicted logP ~2.5, tPSA ~94 Angstrom2), the compound is expected to have moderate to good bioavailability when administered orally or intraperitoneally. Its solubility in DMSO is >100 mg/mL, but aqueous solubility is likely low. For in vivo studies, the compound should be formulated with solubilizing agents such as PEG400, Kolliphor EL, or cyclodextrins to achieve sufficient systemic exposure. Based on related CDK7 inhibitors, plasma half-life in mice is typically 1-4 hours. A standard PK study in rats or mice would involve collecting blood samples at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after a single oral and IV dose. Compound concentrations are quantified by LC-MS/MS. Key parameters such as Cmax, Tmax, AUC, clearance, and volume of distribution would then be calculated. For tissue distribution, brain, liver, kidney, lung, and tumor samples may also be analyzed.
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| Toxicity/Toxicokinetics |
Comprehensive toxicology data for CDK7/12-IN-1 are not available in the public domain, as the compound is a research tool not intended for clinical use. However, given its mechanism of inhibiting transcriptional CDKs, dose-limiting toxicities may include bone marrow suppression and gastrointestinal toxicity, as observed with other transcriptional inhibitors. In cell viability assays, CDK7/12-IN-1 is generally well-tolerated at concentrations that inhibit CDK7, but high concentrations may cause off-target effects. A typical acute toxicity study would involve a single ascending dose (e.g., 50, 150, 500 mg/kg) administered orally to mice, followed by 14 days of observation. Sub-chronic studies (28 days) with daily dosing would include hematology (complete blood count), serum chemistry (liver and kidney function markers), and histopathology of major organs. The compound should be handled with care, as it is a potent enzyme inhibitor. Standard personal protective equipment (gloves, lab coat, goggles) should be used. No data on mutagenicity or genotoxicity are available.
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| References | |
| Additional Infomation |
CDK7/12-IN-1 is a research compound for laboratory use only and is not approved for human therapy. It is a valuable chemical probe for studying the roles of CDK7 and CDK12 in cancer biology and transcription regulation. The compound is available with purity typically >98% and is stored as a powder at -20degC. For in vitro studies, stock solutions are prepared in DMSO (e.g., 10 or 50 mM) and stored at -80degC. The compound is soluble in DMSO at 100 mg/mL. It is not listed in any clinical trial databases. Researchers using this compound should be aware that its selectivity is not absolute (CDK12 is inhibited with ~100-fold less potency than CDK7), and careful interpretation of results is necessary. The compound is part of ongoing efforts to develop effective CDK7/12 inhibitors as anti-cancer therapeutics, particularly for cancers that are dependent on high rates of transcription and are sensitive to transcriptional perturbation.
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| Molecular Formula |
C25H34N8O
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| Molecular Weight |
462.59
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| Exact Mass |
462.285
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| CAS # |
2654075-94-0
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| PubChem CID |
156525415
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| Appearance |
White to light brown solid powder
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| LogP |
3.6
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
667
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| Defined Atom Stereocenter Count |
2
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| SMILES |
N1CC[C@H](CNC2C=C(NCC3N4C(=NC=3C)C=C(C)C=C4)N3N=CC(C(C)C)=C3N=2)[C@@H](O)C1
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| InChi Key |
IHXKZRXUGKSPTO-NQIIRXRSSA-N
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| InChi Code |
InChI=1S/C25H34N8O/c1-15(2)19-12-29-33-23(28-13-20-17(4)30-24-9-16(3)6-8-32(20)24)10-22(31-25(19)33)27-11-18-5-7-26-14-21(18)34/h6,8-10,12,15,18,21,26,28,34H,5,7,11,13-14H2,1-4H3,(H,27,31)/t18-,21+/m1/s1
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| Chemical Name |
(3R,4R)-4-[[[7-[(2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methylamino]-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol
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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 (~216.17 mM)
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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 | 2.1617 mL | 10.8087 mL | 21.6174 mL | |
| 5 mM | 0.4323 mL | 2.1617 mL | 4.3235 mL | |
| 10 mM | 0.2162 mL | 1.0809 mL | 2.1617 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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