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| Targets |
Ki: COX-1:2.3 nM; COX-2:3 nM; COX-4:2.9 nM
AG-024322 targets cyclin-dependent kinases (CDKs), specifically CDK1, CDK2, and CDK4. CDKs are a family of serine/threonine kinases that play a critical role in regulating the cell cycle. CDK1 is essential for the G2/M transition, CDK2 is important for the G1/S transition, and CDK4 is involved in the G1 phase progression. By inhibiting these CDKs, AG-024322 disrupts cell cycle progression, leading to cell cycle arrest and inhibition of cell proliferation. AG-024322 is an ATP-competitive inhibitor, meaning it binds to the ATP-binding site of the CDKs, preventing ATP binding and kinase activity. The Ki values for CDK1, CDK2, and CDK4 are in the 1-3 nM range, indicating high potency. |
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| ln Vitro |
At concentrations below 3 μM, AG-024322 (0.1-30 μM; 24 hours) is less hazardous. The ATP concentration of human PBMC is used to determine their vitality, and the TC50 value of these cells is 1.4 μM [2]. On HCT-116 cells, AG-024322 (0-120 nM) inhibits cell proliferation. With an IC50 of 120 nM in functional cellular tests, it is marginally less powerful [2].
In vitro studies have demonstrated that AG-024322 is a potent inhibitor of CDK1, CDK2, and CDK4. It inhibits these kinases with Ki values in the 1-3 nM range. In cell-based assays, AG-024322 shows growth inhibitory effects on HCT-116 cells with an IC50 of 120 nM. The compound shows low toxicity to human PBMCs at concentrations below 3 μM, with a TC50 of 1.4 μM. AG-024322 induces apoptosis in cancer cell lines, as evidenced by the activation of caspases and the cleavage of PARP. These in vitro findings establish AG-024322 as a potent pan-CDK inhibitor with antitumor activity. |
| ln Vivo |
AG-024322 (IV; 2, 6, and 10 mg/kg; 5 days) had a mean plasma AUC (0-24.5) of 2.11 gh/mL and no side effects at 2 mg/kg. produces lymphocyte depletion and whole-blood bone marrow cytopenia at 6 mg/kg. Additionally, at 10 mg/kg, tubular degeneration was caused by vascular injury at the injection site [1]. Established human tumor xenografts are inhibited in growth by AG-024322 (20 mg/kg) by 32% to 86.4% tumor growth inhibition (TGI). It also demonstrates anticancer effects that are dose-dependent [3]. The MV522 tumor model showed 65% TGI caused by AG-024322 (20 mg/kg). At half the maximum tolerable dosage (MTD), it produced 52% TGI, and at 1/4 of the MTD, it just slightly exhibited antitumor activity [3].
In vivo studies have shown that AG-024322 exhibits broad-spectrum antitumor activity and clear target regulation. In preclinical models, the compound has been shown to produce cell-cycle arrest and antitumor activity. In cynomolgus monkeys, AG-024322 was administered at doses of 2, 6, and 10 mg/kg by intravenous infusion for 5 days. At doses greater than 6 mg/kg, dose-dependent pancytopenic bone marrow hypocellularity and lymphoid depletion in lymph nodes, spleen, and/or thymus were observed. The no-adverse-effect dose was 2 mg/kg, associated with an overall mean plasma AUC(0-24.5) of 2.11 µg h/mL. These studies demonstrate the in vivo activity and potential toxicity of AG-024322. |
| Enzyme Assay |
The in vitro enzyme assay for AG-024322 measures its inhibition of CDK1, CDK2, and CDK4 kinase activity. In a typical assay, recombinant CDK/cyclin complexes (e.g., CDK1/cyclin B, CDK2/cyclin A, CDK4/cyclin D) are incubated with a peptide substrate and ATP in the presence of varying concentrations of AG-024322. The incorporation of phosphate into the substrate is measured using a radiometric (e.g., 33P-ATP) or fluorescent method. The inhibition of kinase activity is calculated, and the Ki is determined from the dose-response curve. The Ki values for CDK1, CDK2, and CDK4 are in the 1-3 nM range. These assays provide a quantitative measure of AG-024322's potency at its molecular targets.
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| Cell Assay |
In vitro cell-based assays for AG-024322 are used to study its effects on cell cycle progression and cell viability. A common assay involves treating cancer cell lines (e.g., HCT-116 colon cancer cells) with varying concentrations of AG-024322. Cell viability is assessed using assays such as MTT or CellTiter-Glo, and the IC50 for growth inhibition is determined. Cell cycle analysis is performed by flow cytometry after staining cells with propidium iodide. The induction of apoptosis is measured using Annexin V staining or caspase-3/7 activation assays. The phosphorylation of CDK substrates, such as retinoblastoma protein (Rb), is assessed by Western blotting to confirm target engagement. These cell-based assays confirm that AG-024322 inhibits CDK activity and exerts anti-proliferative and pro-apoptotic effects in cancer cells.
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| Animal Protocol |
Animal/Disease Models: Male and female cynomolgus monkeys[1]
Doses: 2, 6, and 10 mg/kg (Toxicity analysis) Route of Administration: intravenous (iv) infusion; 5 days Experimental Results: Resulted in dose-dependent pancytic bone marrow hypocellularity and lymphoid depletion in lymph nodes , spleen, and/or thymus at >6 mg/kg. In vivo animal experiments for AG-024322 have been conducted in preclinical models, including xenograft models and toxicology studies in cynomolgus monkeys. In xenograft models, AG-024322 is administered to mice bearing human tumor xenografts, and tumor growth is monitored. In toxicology studies, cynomolgus monkeys are administered AG-024322 by intravenous infusion at various doses (2, 6, and 10 mg/kg) for 5 days. Hematological parameters, including complete blood counts, are monitored. At the end of the study, bone marrow and lymphoid tissues are examined histologically. The no-adverse-effect dose is determined based on the observed toxicities. These studies provide critical data on the in vivo efficacy and safety of AG-024322. |
| ADME/Pharmacokinetics |
AG-024322 has a molecular weight of 418.44 g/mol and a molecular formula of C23H20F2N6. It is a solid compound. AG-024322 is soluble in DMSO at 80 mg/mL (191.19 mM). For storage, it is recommended to keep the powder at -20°C for up to 3 years or in solvent at -80°C for up to 1 year. For in vivo administration, a common formulation includes 10% DMSO, 40% PEG300, 5% Tween 80, and 45% saline. The density is predicted to be 1.361 g/cm³. Pharmacokinetic properties such as half-life, bioavailability, and tissue distribution have been studied in preclinical models. The no-adverse-effect dose in cynomolgus monkeys was 2 mg/kg, associated with an overall mean plasma AUC(0-24.5) of 2.11 µg h/mL.
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| Toxicity/Toxicokinetics |
AG-024322 has been evaluated in preclinical toxicology studies. In cynomolgus monkeys, administration of AG-024322 at doses greater than 6 mg/kg resulted in dose-dependent pancytopenic bone marrow hypocellularity and lymphoid depletion in lymph nodes, spleen, and/or thymus. The no-adverse-effect dose was 2 mg/kg. These findings indicate that the compound's mechanism of action—inhibition of CDKs involved in cell cycle progression—can lead to myelosuppression and lymphoid depletion, which are expected on-target toxicities of pan-CDK inhibitors. As with all research chemicals, standard laboratory safety precautions should be followed when handling AG-024322.
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| References |
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| Additional Infomation |
AG-024322 has been used in clinical trials investigating non-Hodgkin's lymphoma and cancer treatment.
AG-024322, a CDK1/2/4 inhibitor, is a cyclin-dependent kinase (CDK) inhibitor with antitumor activity. AG-024322 selectively inhibits cyclin-dependent kinases (specifically CDK1, 2, and 4), enzymes that regulate cell cycle progression. Inhibition of CDKs can lead to cell cycle arrest, induce apoptosis, and inhibit DNA replication and tumor cell proliferation. AG-024322 is a research compound and is not approved for any clinical or therapeutic use. It is a potent, ATP-competitive pan-CDK inhibitor that inhibits CDK1, CDK2, and CDK4 with Ki values in the 1-3 nM range. AG-024322 shows broad-spectrum antitumor activity and clear target regulation in vivo. It induces apoptosis and can be used in the study of metabolic diseases. The compound's mechanism of action involves inhibiting CDK activity, thereby disrupting cell cycle progression and inhibiting tumor cell proliferation. AG-024322 has been investigated for its potential in cancer therapy, but its development may have been limited by on-target toxicities such as myelosuppression. |
| Molecular Formula |
C23H20F2N6
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| Molecular Weight |
418.44191
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| Exact Mass |
418.172
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| CAS # |
837364-57-5
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| PubChem CID |
135413565
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| Appearance |
White to off-white solid powder
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| LogP |
1.816
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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 |
5
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| Heavy Atom Count |
31
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| Complexity |
611
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
MEKASOQEXYKAKM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H20F2N6/c1-3-26-9-14-10-27-11-17(12(14)2)13-4-5-19-16(6-13)21(31-30-19)23-28-20-8-15(24)7-18(25)22(20)29-23/h4-8,10-11,26H,3,9H2,1-2H3,(H,28,29)(H,30,31)
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| Chemical Name |
N-[[5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-4-methylpyridin-3-yl]methyl]ethanamine
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| Synonyms |
AG024322 AG 024322 AG-24322
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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 (~238.98 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.97 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 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 (5.97 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3898 mL | 11.9491 mL | 23.8983 mL | |
| 5 mM | 0.4780 mL | 2.3898 mL | 4.7797 mL | |
| 10 mM | 0.2390 mL | 1.1949 mL | 2.3898 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00147485 | TERMINATED | Drug: AG-024322 | Lymphoma, Non-Hodgkin Neoplasms |
Pfizer | 2004-12 | Phase 1 |
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