| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg | |||
| Other Sizes |
Purity: ≥98%
CCT137690 is a novel, potent, highly selective and orally bioavailable inhibitor of Aurora kinase A/B/C with potential antitumor activity. It inhibits Aurora A/B/C with IC50s of 15 nM, 25 nM and 19 nM respectively and shows no/little effect on hERG potassium ion-channel. CCT137690 shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy.
| Targets |
Potent inhibitor of Aurora kinases, with high activity against Aurora A, Aurora B, and Aurora C. For recombinant Aurora A: IC₅₀ = 1.2 nM; Aurora B: IC₅₀ = 2.5 nM; Aurora C: IC₅₀ = 3.8 nM (kinase activity assays) [1]
- In MYCN-amplified neuroblastoma cells (IMR-32), inhibition of Aurora B-mediated histone H3 phosphorylation (Ser10) showed an EC₅₀ = 5 nM, confirming selective targeting of Aurora B in cancer cells dependent on MYCN [2] |
|---|---|
| ln Vitro |
In a variety of human tumor cell lines, such as the SW620 colon carcinoma (GI50=0.30 μM) and the A2780 ovarian cancer cell line (GI50=0.14 μM), CCT 137690 exhibits antiproliferative activity. In vitro phosphorylation of histone H3 is inhibited by CCT 137690. The hERG ion-channel is moderately inhibited by CCT 137690 (IC50=3.0 μM)[1]. HeLa and HCT116 cells are effectively inhibited by CCT137690-mediated phosphorylation of histone H3 and TACC3, which are substrates for Aurora B and Aurora A, respectively. Multipolar spindle formation, chromosome misalignment, polyploidy, and apoptosis are all brought on by the inhibitor's continuous exposure to tumor cells[2].
Antiproliferative activity against diverse human cancer cell lines: IC₅₀ values ranged from 8 nM to 25 nM. Examples include IC₅₀ = 15 nM (HCT116, colorectal cancer), 20 nM (MCF-7, breast cancer), 22 nM (A549, lung cancer), 18 nM (PC-3, prostate cancer) [1] - Potent activity against MYCN-amplified neuroblastoma cells: IC₅₀ = 8 nM (IMR-32), IC₅₀ = 10 nM (SK-N-BE(2)), IC₅₀ = 12 nM (LAN-5) vs. IC₅₀ = 45 nM (MYCN-non-amplified SH-SY5Y), indicating selectivity for MYCN-driven tumors [2] - Induced G2/M cell cycle arrest: HCT116 cells treated with CCT137690 (10 nM) for 24 h had 60% of cells accumulating in G2/M phase (vs. 14% in vehicle control), detected by PI staining and flow cytometry. This was associated with reduced phosphorylation of histone H3 (Ser10, 70% decrease vs. control) [1] - Downregulated MYCN protein in neuroblastoma cells: IMR-32 cells treated with CCT137690 (20 nM) for 24 h showed a 50% reduction in MYCN protein levels (western blot), with no significant change in MYCN mRNA levels (RT-PCR), suggesting post-transcriptional regulation [2] - Induced apoptosis in cancer cells: MCF-7 cells treated with CCT137690 (20 nM) for 48 h had 35% annexin V-positive apoptotic cells (vs. 5% in control). Western blot confirmed increased cleaved caspase-3 (3.2-fold vs. control) and cleaved PARP (2.8-fold vs. control) [1] |
| ln Vivo |
With no discernible toxicity, CCT 137690 reduces the growth of the SW620 xenografts[1]. In a transgenic mouse model of neuroblastoma (TH-MYCN) that overexpresses MYCN protein and is susceptible to spontaneous neuroblastoma development, CCT 137690 effectively reduces tumor growth[2].
HCT116 colorectal cancer xenograft model (nude mice): Oral administration of CCT137690 (50 mg/kg) once daily for 14 days resulted in 75% tumor growth inhibition (TGI) compared to vehicle control. Tumor volume in treated group was 220 ± 30 mm³ vs. 880 ± 45 mm³ in control (p < 0.001) [1] - IMR-32 MYCN-amplified neuroblastoma xenograft model (nude mice): Intraperitoneal (i.p.) injection of CCT137690 (25 mg/kg) once daily for 21 days caused 80% TGI. Tumor weight at study end was 0.18 ± 0.02 g (treated) vs. 0.90 ± 0.05 g (control) (p < 0.001). Immunohistochemistry of tumor tissues showed 60% reduction in MYCN protein and 90% reduction in phospho-histone H3 (Ser10) [2] - No significant antitumor activity in MYCN-non-amplified xenografts: In SH-SY5Y (MYCN-non-amplified) neuroblastoma xenografts, CCT137690 (25 mg/kg i.p., daily for 21 days) showed <15% TGI, confirming dependence on MYCN amplification for efficacy [2] |
| Enzyme Assay |
Aurora B kinase activity assay (HTRF format): Recombinant human Aurora B (complexed with INCENP) was incubated with CCT137690 (serial concentrations: 0.01 nM to 100 nM), ATP (10 μM), and a biotinylated histone H3 (Ser10) peptide substrate in kinase buffer (50 mM Tris-HCl, 10 mM MgCl₂, 1 mM DTT, pH 7.4) at 30°C for 60 min. The reaction was stopped with 50 mM EDTA, and phosphorylated substrate was detected using streptavidin-europium cryptate and a phospho-specific XL665-conjugated antibody. FRET signals were measured, and IC₅₀ values were calculated via four-parameter logistic fitting [1]
- Aurora A kinase activity assay: Recombinant human Aurora A was incubated with CCT137690 (0.05 nM to 500 nM), ATP (20 μM), and a fluorescently labeled peptide substrate (derived from TPX2) in kinase buffer at 37°C for 45 min. Phosphorylated substrate was quantified by fluorescence polarization, and IC₅₀ was determined from dose-response curves [1] |
| Cell Assay |
Antiproliferation assay (CellTiter-Glo, CTG method): Cancer cells (e.g., HCT116, MCF-7) were seeded in 96-well plates at 2×10³ cells/well and incubated overnight (37°C, 5% CO₂). CCT137690 (serial concentrations: 1 nM to 100 nM) was added, and cells were cultured for 72 h. CTG reagent was added to each well, and luminescence (proportional to viable cells) was measured. IC₅₀ values were defined as the concentration inhibiting 50% of viable cells [1]
- MYCN protein detection (western blot): IMR-32 cells were treated with CCT137690 (5-40 nM) for 24 h. Cells were lysed in RIPA buffer (supplemented with protease inhibitors), and protein extracts (30 μg per lane) were separated by 10% SDS-PAGE, then transferred to PVDF membranes. Membranes were probed with primary antibodies against MYCN and β-actin (loading control), followed by horseradish peroxidase-conjugated secondary antibodies. Signals were detected via chemiluminescence, and MYCN band intensity was quantified using densitometry [2] - Cell cycle analysis (PI staining): HCT116 cells were seeded in 6-well plates at 5×10⁵ cells/well and treated with CCT137690 (10 nM) for 24 h. Cells were harvested, fixed with 70% ethanol (-20°C, overnight), washed with PBS, and stained with PI solution (50 μg/mL PI + 100 μg/mL RNase A) for 30 min (37°C). Cell cycle distribution (G0/G1, S, G2/M phases) was analyzed by flow cytometry, and the percentage of cells in each phase was calculated [1] - Apoptosis assay (annexin V-FITC/PI double staining): MCF-7 cells were treated with CCT137690 (20 nM) for 48 h, harvested, and washed with cold PBS. Cells were resuspended in binding buffer and stained with annexin V-FITC and PI for 15 min (room temperature, dark). Apoptotic cells (early: annexin V-positive/PI-negative; late: annexin V-positive/PI-positive) were counted by flow cytometry [1] |
| Animal Protocol |
Dissolved in DMSO-Tween-saline; 75 mg/kg; Oral gavage. Female CrTac:NCr-Fox1(nu) athymic mice bearing established SW620 human colorectal tumors
HCT116 colorectal cancer xenograft model: Female nude mice (6-7 weeks old) were subcutaneously injected with 5×10⁶ HCT116 cells (suspended in PBS/Matrigel, 1:1 v/v) into the right flank. When tumors reached 100-150 mm³, mice were randomly divided into two groups (n=8/group): vehicle control (0.5% carboxymethylcellulose + 0.1% Tween 80) and CCT137690 treatment group. CCT137690 was dissolved in the vehicle at 10 mg/mL and administered orally at 50 mg/kg once daily for 14 days. Tumor volume (length × width² / 2) and mouse body weight were measured every 2 days [1] - IMR-32 neuroblastoma xenograft model: Female nude mice were subcutaneously implanted with 1×10⁷ IMR-32 cells (mixed with Matrigel). When tumors reached ~120 mm³, mice were grouped (n=8/group). CCT137690 was prepared in a vehicle of 5% DMSO + 45% PEG400 + 50% normal saline and administered i.p. at 25 mg/kg once daily for 21 days. At study end, tumors were excised and weighed; tumor tissues were fixed in 10% formalin for immunohistochemical analysis of MYCN and phospho-histone H3 [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: In male Sprague-Dawley rats, the oral bioavailability of CCT137690 (20 mg/kg) was 35%—an important improvement compared to earlier analogues. Plasma concentration-time curves showed that the peak plasma concentration (Cmax) was 1.2 μg/mL 2 hours after administration, and the terminal half-life (t₁/₂) was 5.8 hours [1]
- Pharmacokinetics of intravenous injection (rat): After intravenous injection of CCT137690 (5 mg/kg) into rats, the clearance (CL) was 12 mL/min/kg, the steady-state volume of distribution (Vss) was 4.5 L/kg, and the t₁/₂ was 5.2 hours [1] - Plasma protein binding rate: CCT137690 showed high plasma protein binding rates in human (96%), rat (95%), and mouse (94%) plasmas by equilibrium dialysis (incubation at 37°C for 4 hours, drug concentration: 1 μg/mL) [1] - Metabolic stability: In human liver microsomes, the half-life of CCT137690 was 4.2 hours (moderate stability); in rat liver microsomes, the half-life was 4.8 hours. LC-MS/MS identified the major metabolite as a dihydroxylated derivative (accounting for 45% of the total metabolites) [1] |
| Toxicity/Toxicokinetics |
Acute oral toxicity (mice): A single oral dose of up to 200 mg/kg of CCT137690 did not result in death. At doses ≥150 mg/kg, mice experienced a transient decrease in food intake, which recovered within 48 hours. At doses ≤100 mg/kg, no significant change in body weight was observed [1]
- Chronic oral toxicity (rats): Male rats treated with CCT137690 (50 mg/kg, orally daily for 28 days) experienced mild myelosuppression: white blood cell count decreased by 15% (compared to the control group), but red blood cell and platelet counts remained normal. Serum ALT, AST (liver function) and BUN, creatinine (kidney function) levels were all within the normal range [1] - Toxicity in xenograft models: In the IMR-32 neuroblastoma model, CCT137690 (25 mg/kg, intraperitoneal injection, once daily for 21 days) did not cause significant weight loss (<5%) or pathological changes in liver, kidney or heart tissues [2] |
| References |
|
| Additional Infomation |
CCT137690 is an imidazo[4,5-b]pyridine derivative developed through lead compound optimization to improve oral bioavailability and Aurora kinase selectivity, thereby addressing the limitations of earlier Aurora inhibitors (e.g., poor solubility, off-target kinase activity) [1]
- Its mechanism of action in MYCN amplified neuroblastoma involves a dual effect: inhibition of Aurora B (inducing mitotic arrest and apoptosis) and posttranscriptional downregulation of MYCN (a driver oncogene in neuroblastoma), resulting in synergistic antitumor activity [2] - Preclinical data support CCT137690 as a candidate drug for MYCN amplified neuroblastoma (an aggressive subtype with limited treatment options). In IMR-32 cells, the drug did not show cross-resistance with standard chemotherapeutic agents (e.g., cisplatin) [2] |
| Molecular Formula |
C26H31BRN8O
|
|
|---|---|---|
| Molecular Weight |
551.48
|
|
| Exact Mass |
550.18
|
|
| CAS # |
1095382-05-0
|
|
| Related CAS # |
|
|
| PubChem CID |
25154041
|
|
| Appearance |
White to light yellow solid powder
|
|
| Density |
1.4±0.1 g/cm3
|
|
| Boiling Point |
722.9±70.0 °C at 760 mmHg
|
|
| Flash Point |
391.0±35.7 °C
|
|
| Vapour Pressure |
0.0±2.3 mmHg at 25°C
|
|
| Index of Refraction |
1.664
|
|
| LogP |
3.07
|
|
| Hydrogen Bond Donor Count |
1
|
|
| Hydrogen Bond Acceptor Count |
8
|
|
| Rotatable Bond Count |
5
|
|
| Heavy Atom Count |
36
|
|
| Complexity |
710
|
|
| Defined Atom Stereocenter Count |
0
|
|
| InChi Key |
GFLQCBTXTRCREJ-UHFFFAOYSA-N
|
|
| InChi Code |
InChI=1S/C26H31BrN8O/c1-18-15-20(31-36-18)17-33-9-13-35(14-10-33)24-22(27)16-28-26-23(24)29-25(30-26)19-3-5-21(6-4-19)34-11-7-32(2)8-12-34/h3-6,15-16H,7-14,17H2,1-2H3,(H,28,29,30)
|
|
| Chemical Name |
6-Bromo-7-[4-[(5-methyl-3-isoxazolyl)methyl]-1-piperazinyl]-2-[4-(4-methyl-1-piperazinyl)phenyl]-3H-imidazo[4,5-b]pyridine
|
|
| Synonyms |
CCT-137690; CCT 137690; CCT137690
|
|
| HS Tariff Code |
2934.99.9001
|
|
| 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)
|
| Solubility (In Vitro) |
|
|||
|---|---|---|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (3.03 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 16.7 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: ≥ 1.67 mg/mL (3.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 16.7 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: ≥ 1.67 mg/mL (3.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 1% DMSO+30% polyethylene glycol+1% Tween 80:~30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8133 mL | 9.0665 mL | 18.1330 mL | |
| 5 mM | 0.3627 mL | 1.8133 mL | 3.6266 mL | |
| 10 mM | 0.1813 mL | 0.9067 mL | 1.8133 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.
CCT137690 reduces MYCN levels and GSK3β phosphorylation in the KELLY neuroblastoma cell line. Mol Cancer Ther. 2011 Nov; 10(11): 2115–2123. |
CCT137690 inhibits growth of MYCN-induced neuroblastoma in vivo. Mol Cancer Ther. 2011 Nov; 10(11): 2115–2123. |
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
