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| Targets |
CA-224's primary target is the Cdk4–cyclin D1 complex. Cyclin-dependent kinase 4 (Cdk4) is a key regulator of the cell cycle, and its activity is dependent on its association with cyclin D1. This complex promotes the phosphorylation of the retinoblastoma protein (Rb), leading to the release of E2F transcription factors and the progression of the cell cycle from G1 to S phase. By inhibiting this complex, CA-224 induces cell cycle arrest in the G0/G1 phase.
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| ln Vitro |
CA224 (Compound 1) (48 hours) treatment against human cancer cell lines demonstrated antiproliferative efficacy [1]. CA224 (18–48 hours) selectively destroys SV40 large T antigen-transformed normal mouse embryonic liver cells (BNL S A.8) and inhibits the growth of cancer cells in the G0/G1 and G2/M phases of the cell cycle [1][2]. Tubulin polymerization is inhibited and stable tubulin depolymerization is enhanced by CA224 (0–4 µM, 30 min) [1]. Cancer cells undergo apoptosis when exposed to CA224 (0-72 h) [1]. Inhibiting CYP3A4, CYP2D6, CYP2C9, and CYP2C19 by 50%, 14%, 51%, and 19%, respectively, is the effect of CA224 (10 μM) [1].
In vitro, CA-224 is a selective and orally active Cdk4–cyclin D1 inhibitor with an IC50 of 6.2 µM. It induces cell apoptosis and shows antitumor activity. It blocks the growth of cancer cells at the G0/G1 phase of the cell cycle. It has also been reported to block the cell cycle at G2/M phase, which is attributed to its inhibition of tubulin polymerization. |
| ln Vivo |
Significant tumor growth inhibition was demonstrated by CA224 (Compound 1) (100 mg/kg; intraperitoneal injection; once daily for 9 days) without overt toxicity [1].
In vivo, CA-224 has shown antitumor activity. As an orally active compound, it can be administered to animal models to evaluate its efficacy. Its ability to inhibit Cdk4–cyclin D1 and induce apoptosis translates to tumor growth inhibition in vivo. It is being investigated for its potential in treating cancers such as breast cancer, where Cdk4 is often overexpressed. |
| Enzyme Assay |
The in vitro activity of CA-224 against Cdk4–cyclin D1 is determined using cell-free kinase assays. In a typical protocol, the Cdk4–cyclin D1 complex is incubated with a substrate (e.g., retinoblastoma protein fragment) and ATP in the presence or absence of CA-224. The phosphorylation of the substrate is then measured, and the IC50 is calculated.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: LS174T, PC-3, MiaPaCa, A549, Calu-1, NCI-H460, NCI-H1299, NCI-H358, BNL CL2 and BNL SV A.8 Tested Concentrations: Incubation Duration: 48 hrs (hours) Experimental Results: demonstrated anti-proliferative activity against LS174T, PC-3, MiaPaCa, A549, Calu-1, NCI-H460, NCI- with IC50 values of 3.5, 6.2, 4.0, 3.5, 11.5, 2.0, 2.5, 2.2, 2.6 and 3.8 uM are H1299, NCI-H358, BNL CL2 and BNL SV A.8 respectively. Cell cycle analysis[1][2] Cell Types: A549, NCI-H1299, NCI-H358, BNL CL2, BNL SV A.8 and Calu-1 Tested Concentrations: IC50 concentration (IC70 for Calu-1) Incubation Duration: 24 hrs (hours) 18 hrs (hours) for NCI-H358 and 48 hrs (hours) for BNL CL2 and BNL SV for A549, NCI-H1299 and Calu-1 A.8 Experimental Results: Deep blockade was induced at G2/M in A549 and NCI-H1299 cells. Maintenance of nocodazole- and paclitaxel-induced G2/M arrest in NCI-H358 cells. BNL CL2 cells exhibit significant G2/M phase arrest. In BNL S A.8 cells 31% of cells were detected in sub-G1 phase (control: 0%). G0/G1 blockade is preserved in serum- Cellular assays for CA-224 involve studying its effect on cell cycle progression and apoptosis. In a typical protocol, cancer cells are treated with increasing concentrations of CA-224. Cell cycle distribution is analyzed by flow cytometry, and apoptosis is quantified by staining with Annexin V and propidium iodide. The compound's ability to induce G0/G1 arrest and apoptosis is assessed. |
| Animal Protocol |
Animal/Disease Models: Severe combined immunodeficiency (SCID) mice, which lack T and B immune cells. Male mice weighing 18~25 g and 6~8 weeks old were injected subcutaneously (sc) (sc) with HCT-116, and female mice weighing 15~24 g and 6~8 weeks old were injected subcutaneously (sc) (sc) with NCI-H460[1].
Doses: 100 mg/kg Route of Administration: intraperitoneal (ip) injection, one time/day for 9 days. Experimental Results: It demonstrated significant tumor growth inhibition in both HCT-116 and NCI-H460 tumor models, and there was no significant decrease in body weight. Animal/Disease Models: balb/c (Bagg ALBino) mouse [1] Doses: 10 mg/kg (oral) or 1.0 mg/kg (iv) Route of Administration: Oral or intravenous (iv) (iv)(pharmacokinetic/PK/PK analysis) Experimental Results: After IV and PO Determination of administrative pharmacokinetic/PK/PK parameters of CA224 [1]. Parameter IV (1 mg/kg) Oral (10 mg/kg) t1/2,β (h) 0.33 1.16 AUC0-t (ng·h/mL) 187 172 AUC0-∞ (ng·h/mL) 189 182 Cmax (ng/mL) 371 190 Vd (L/Kg) 2.52 nd Vdss (L/Kg) 1.76 nd CL (mL/min/kg) 88.3 nd Bioavailability - 9.6% t1/2,β Time point 0.5 consid The in vivo efficacy of CA-224 is evaluated in xenograft mouse models. In these studies, human tumor cells are implanted subcutaneously into immunodeficient mice. When tumors reach a certain size, the animals are treated with CA-224 via oral gavage. Tumor growth is monitored by caliper measurements, and tumor weights are assessed at the end of the study. The compound's ability to inhibit tumor growth is compared to control groups. |
| ADME/Pharmacokinetics |
CA-224 is an orally active, small-molecule inhibitor of Cdk4–cyclin D1. It has a molecular weight of 354.44 and a molecular formula of C₂₄H₂₂N₂O₂. Its oral bioavailability makes it a promising candidate for therapeutic development. Detailed pharmacokinetic parameters (e.g., half-life, Cmax) would be characterized in preclinical studies.
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| Toxicity/Toxicokinetics |
The toxicity of CA-224 is related to its mechanism of action. As a Cdk4–cyclin D1 inhibitor, it can affect the proliferation of normal cells, particularly in tissues with high turnover rates, such as the bone marrow and gastrointestinal tract. This can lead to side effects such as myelosuppression and gastrointestinal toxicity. These effects would be carefully evaluated during drug development.
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| References |
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| Additional Infomation |
CA-224 (Compound 1) is a selective and orally active Cdk4–cyclin D1 inhibitor with an IC50 of 6.2 µM. It induces cell apoptosis and shows antitumor activity. It blocks the growth of cancer cells at the G0/G1 phase of the cell cycle. It is a research compound being investigated for its potential in cancer therapy, but it is not an approved drug.
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| Molecular Formula |
C24H22N2O
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|---|---|
| Molecular Weight |
354.444
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| Exact Mass |
354.173
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| CAS # |
883561-04-4
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| PubChem CID |
11610059
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| Appearance |
White to off-white solid powder
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| LogP |
5.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
1
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
479
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1C2=C(C=CC=C2)C(CCN(C)C(C2=CC=C(C3=CC=CC=C3)C=C2)=O)=C1
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| InChi Key |
CPKLVRIYXBROSG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H22N2O/c1-26(16-15-21-17-25-23-10-6-5-9-22(21)23)24(27)20-13-11-19(12-14-20)18-7-3-2-4-8-18/h2-14,17,25H,15-16H2,1H3
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| Chemical Name |
N-[2-(1H-indol-3-yl)ethyl]-N-methyl-4-phenylbenzamide
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| Synonyms |
CA-224; CA 224; CA224
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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 (~282.14 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.05 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 | 2.8214 mL | 14.1068 mL | 28.2135 mL | |
| 5 mM | 0.5643 mL | 2.8214 mL | 5.6427 mL | |
| 10 mM | 0.2821 mL | 1.4107 mL | 2.8214 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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