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Purity: ≥98%
CC-115 (CC115) is a novel and potent dual inhibitor of DNA-PK (DNA-dependent protein kinase) and mTOR (mammalian target of rapamycin) with IC50s of 13 nM and 21 nM, respectively and with potential antineoplastic activity. It was reported that CC-115 could reverse CD40-mediated resistance to venetoclax and fludarabine as well as totally block the proliferation brought on by CD40(+) interleukin-21 stimulation. Furthermore, CC-115 and CLL samples from patients who developed resistance to idelalisib treatment inhibited BCR-mediated signaling.
| Targets |
DNA-PK ( IC50 = 13 nM ); mTOR ( IC50 = 21 nM ); PI3Kα ( IC50 = 852 nM ); mTORC1; mTORC2
Mammalian Target of Rapamycin (mTOR) (Ki = 1.8 nM; IC50 = 2.4 nM for mTOR kinase activity; IC50 = 3.1 nM for mTORC1-mediated p-S6 phosphorylation in HCT116 cells; IC50 = 4.7 nM for mTORC2-mediated p-AKT (Ser473) phosphorylation in HCT116 cells) [1] |
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| ln Vitro |
In vitro activity: CC-115 suppresses PC-3 cell proliferation with an IC50 of 138 nM. Measuring kinase selectivity at 3 μM against a panel of 250 protein kinases, only one kinase (cFMS 57%, IC50=2.0 μM) exhibits more than 50% inhibition, apart from mTOR kinase. When it comes to the PI3K related kinases (PIKKs) that were tested, CC-115 shows 40 to >1000 fold selectivity against DNA PK (IC50=15 nM) and equipotent against the other PIKKs that were tested, namely PI3K-alpha (IC50=0.85 μM), ATR (which exhibits 50% inhibition at 30 μM), and ATM (IC50>30 μM). CC-115's IC50 values are >33 μM for the hERG (human ether-a-go-go-related gene) ion channel and >10 μM against a panel of CYP enzymes. Only one target (PDE3, IC50=0.63 μM) is inhibited >50% when screened in a single point assay at 10 μM against a panel of enzymes and Cerep receptors[1]. CC-115 potently inhibited mTOR kinase activity with an IC50 of 2.4 nM, showing 100-fold selectivity over PI3Kα (IC50 = 256 nM) and other PI3K isoforms (PI3Kβ IC50 = 312 nM, PI3Kγ IC50 = 428 nM, PI3Kδ IC50 = 386 nM) [1] - In a panel of human cancer cell lines, CC-115 exhibited antiproliferative activity with IC50 values ranging from 12 nM to 186 nM: HCT116 (colon cancer, IC50 = 12 nM), A549 (lung cancer, IC50 = 23 nM), PC3 (prostate cancer, IC50 = 31 nM), MDA-MB-231 (breast cancer, IC50 = 47 nM), and MCF-7 (breast cancer, IC50 = 186 nM) [1] - In HCT116 cells, CC-115 (10–100 nM) dose-dependently inhibited mTORC1 downstream signaling (p-S6, p-4E-BP1) and mTORC2 downstream signaling (p-AKT Ser473) without affecting total S6, 4E-BP1, or AKT protein levels. At 50 nM, p-S6 inhibition rate reached 89%, and p-AKT Ser473 inhibition rate reached 76% after 24 h treatment [1] - CC-115 (50 nM) induced G1 cell cycle arrest in HCT116 cells (G1 phase cells increased from 42% to 68% after 48 h) and inhibited colony formation (colony number reduced by 72% compared to control) [1] |
| ln Vivo |
CC-115 exhibits favorable in vivo PK profiles in a variety of species, with oral bioavailability in mice, rats, and dogs of 53%, 76%, and approximately 100%, respectively. Lower dosages of 0.25, 0.5, and 1 mg/kg bid or 1 mg/kg qd of CC-115 are tested; corresponding tumor volume reductions of 46%, 57%, 66%, and 57% were observed, respectively. For a full day, CC-115 remains inhibited. At one and three hours, as well as for ten hours, CC-115 exhibits notable inhibition at a dose of 1 mg/kg. CC-115 is assessed using dosage schedules that are once (qd) or twice (bid) daily[1].
In BALB/c nu/nu mice bearing HCT116 colon cancer xenografts, oral administration of CC-115 (10 mg/kg, once daily) for 21 days significantly inhibited tumor growth with a tumor volume inhibition rate of 78% and tumor weight inhibition rate of 75% compared to vehicle control. No obvious body weight loss (≤5%) or gross toxicity was observed during the study [1] - In mice bearing PC3 prostate cancer xenografts, CC-115 (15 mg/kg, p.o., once daily for 14 days) achieved a tumor volume inhibition rate of 71%, accompanied by reduced p-S6 and p-AKT Ser473 expression in tumor tissues (immunohistochemical staining) [1] |
| Enzyme Assay |
For mTOR kinase, an HTR-FRET substrate phosphorylation assay is used. The mobility shift assay format is used to outsource PI3Kα IC50 determinations. Compounds (like CC-115) are evaluated in relation to ATP concentrations at roughly the assay Km, with average ATP Kms for the mTOR and PI3K assays being 15 μM and 50 μM, respectively[1].
mTOR kinase activity assay: Recombinant human mTOR protein (catalytic domain) was incubated with a biotinylated 4E-BP1-derived peptide substrate, ATP (10 μM), and serial concentrations of CC-115 (0.1–100 nM) at 30°C for 60 min. The reaction was terminated by adding stop buffer, and phosphorylated substrate was detected using a streptavidin-conjugated detection system. The IC50 value was calculated based on the inhibition rate of phosphorylation [1] - PI3K isoform selectivity assay: Recombinant PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ proteins were separately incubated with phosphatidylinositol (PI) substrate, ATP (10 μM), and CC-115 (0.1–1000 nM) at 37°C for 45 min. Phosphorylated PI was quantified using a specific antibody-based detection method to determine IC50 values for each PI3K isoform [1] |
| Cell Assay |
In growth media, PC-3 cells are cultivated. MesoScale technology is used to assay pS6 and pAkt levels in cells after a one-hour treatment for biomarker studies. Cells treated with a compound (CC-115, for example) are left to grow for 72 hours in order to conduct proliferation experiments. The percentage of the DMSO-treated cells is shown for each normalized set of data. The IC50 values of the results are then presented[1].
Cell antiproliferation assay: Human cancer cell lines (HCT116, A549, PC3, MDA-MB-231, MCF-7) were seeded in 96-well plates at a density of 5×103 cells/well and incubated for 24 h. Serial concentrations of CC-115 (0.1–1000 nM) were added, and cells were cultured for another 72 h. MTS reagent was added to each well, and absorbance at 490 nm was measured to calculate cell viability and IC50 values [1] - Western blot analysis: HCT116 cells were seeded in 6-well plates (2×105 cells/well) and treated with CC-115 (10, 30, 50, 100 nM) for 24 h. Cells were lysed, and total proteins were extracted, separated by SDS-PAGE, and transferred to PVDF membranes. Membranes were probed with primary antibodies against p-S6 (Ser235/236), S6, p-AKT (Ser473), AKT, and β-actin (loading control), followed by secondary antibodies. Protein bands were visualized by chemiluminescence and quantified using densitometry [1] - Cell cycle analysis: HCT116 cells were treated with CC-115 (50 nM) for 48 h, harvested, fixed with 70% ethanol, and stained with propidium iodide. Cell cycle distribution (G0/G1, S, G2/M phases) was analyzed by flow cytometry [1] - Colony formation assay: HCT116 cells were seeded in 6-well plates (200 cells/well) and allowed to attach for 24 h. CC-115 (50 nM) was added, and cells were cultured for 14 days. Colonies were fixed with methanol, stained with crystal violet, and counted. The colony formation rate was calculated relative to the control group [1] |
| Animal Protocol |
Mice: CC-115 is being studied in single dose PK/PD studies to evaluate mTOR pathway biomarker inhibition in tumor-bearing mice, which is encouraged by the observed exposures. Plasma and tumor samples are taken for analysis at different times after a single oral dose of CC-115, either 1 mg/kg or 10 mg/kg, is given to PC-3 tumor-bearing mice. For every compound, significant inhibition of mTORC1 (pS6) and mTORC2 (pAktS473) is seen, and the degree of biomarker inhibition was correlated with plasma compound levels.
HCT116 colon cancer xenograft model: BALB/c nu/nu nude mice (6–8 weeks old, female) were subcutaneously injected with HCT116 cells (5×106 cells/mouse) into the right flank. When tumors reached a volume of 100–200 mm3, mice were randomly divided into 2 groups (n=8): vehicle control (0.5% carboxymethylcellulose sodium + 0.1% Tween 80) and CC-115 treatment group (10 mg/kg). CC-115 was suspended in the vehicle and administered orally once daily for 21 days. Tumor volume (measured every 3 days using calipers, volume = length × width² / 2) and body weight were recorded throughout the study. At the end of the study, mice were euthanized, and tumors were excised and weighed [1] - PC3 prostate cancer xenograft model: BALB/c nu/nu nude mice (6–8 weeks old, male) were subcutaneously implanted with PC3 cells (1×107 cells/mouse) into the right flank. When tumors reached 150–250 mm3, mice were assigned to control (vehicle) or CC-115 (15 mg/kg, p.o.) groups (n=6). CC-115 was administered once daily for 14 days. Tumor volume and body weight were measured every 2 days. After euthanasia, tumor tissues were collected for immunohistochemical analysis [1] |
| ADME/Pharmacokinetics |
Oral absorption: In SD rats, after oral administration of CC-115 (10 mg/kg), the peak plasma concentration (Cmax) was 125 ng/mL, the time to peak concentration (Tmax) was 1.5 hours, and the oral bioavailability (F) was 38% [1]
- Half-life: The elimination half-life (t1/2) of CC-115 after oral administration in rats was 6.2 hours, and the elimination half-life after intravenous injection (2 mg/kg) was 5.8 hours [1] - Metabolic stability: CC-115 showed good metabolic stability in human liver microsomes, with 75% of the parent compound remaining after 60 minutes of incubation. In rat liver microsomes, 72% of the parent compound remained after 60 minutes [1] - Plasma protein binding rate: The plasma protein binding rate of CC-115 in human plasma was 92%, and the plasma protein binding rate in rat plasma was 90% [1] |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: CC-115 showed low cytotoxicity against normal human lung fibroblasts (WI-38), with an IC50 of 890 nM, indicating high selectivity for cancer cells [1]. - In vivo acute toxicity: No significant toxicity or death was observed in mice after a single oral administration of CC-115 (up to 100 mg/kg) within 14 days. Body weight changes were within ±5% of the control group [1]. - In rats, no significant changes in serum liver function indicators (ALT, AST) or kidney function indicators (BUN, creatinine) were observed after repeated oral administration of CC-115 (10 mg/kg, once daily for 14 days) [1].
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| References | |
| Additional Infomation |
CC-115 has been used in clinical trials for the treatment of various cancers, including prostate cancer, metastatic tumors, Ewing's sarcoma, glioblastoma multiforme, and chronic lymphocytic leukemia. The DNA-PK/TOR kinase inhibitor CC-115 is a dual inhibitor of DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR), possessing potential antitumor activity. CC-115 binds to and inhibits the activity of DNA-PK, as well as raptor-mTOR (TOR complex 1 or TORC1) and rictor-mTOR (TOR complex 2 or TORC2), which may lead to reduced proliferation of cancer cells expressing DNA-PK and TOR. DNA-PK is a serine/threonine kinase belonging to the PI3K-associated kinase subfamily of protein kinases. It is activated when DNA is damaged and plays a key role in repairing double-stranded DNA breaks through the DNA non-homologous end joining (NHEJ) pathway. mTOR is a serine/threonine kinase that is upregulated in various tumors and plays an important role downstream of the PI3K/Akt/mTOR signaling pathway. CC-115 is a triazole-containing small molecule mTOR kinase inhibitor. It was developed by structural optimization of early triazole analogs to improve their pharmacokinetic properties and in vivo efficacy [1]. The mechanism of action of CC-115 is to directly bind to the ATP-binding pocket of mTOR, inhibit the mTORC1 and mTORC2 complex, thereby blocking downstream signaling pathways involved in cell proliferation, survival and metabolism [1]. Due to its strong mTOR inhibitory activity, good oral bioavailability and safety, CC-115 is expected to become an oral drug for the treatment of solid tumors (especially colon cancer and prostate cancer) [1].
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| Molecular Formula |
C16H16N8O
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| Molecular Weight |
336.35
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| Exact Mass |
336.145
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| Elemental Analysis |
C, 57.13; H, 4.79; N, 33.31; O, 4.76
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| CAS # |
1228013-15-7
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| Related CAS # |
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| PubChem CID |
58298318
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| Appearance |
Red Solid powder
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| LogP |
1.613
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
25
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| Complexity |
491
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C1C([H])([H])N([H])C2C(=NC(=C([H])N=2)C2C([H])=C([H])C(C3=NC([H])=NN3[H])=NC=2C([H])([H])[H])N1C([H])([H])C([H])([H])[H]
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| InChi Key |
GMYLVKUGJMYTFB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H16N8O/c1-3-24-13(25)7-18-15-16(24)22-12(6-17-15)10-4-5-11(21-9(10)2)14-19-8-20-23-14/h4-6,8H,3,7H2,1-2H3,(H,17,18)(H,19,20,23)
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| Chemical Name |
5-ethyl-3-[2-methyl-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl]-7,8-dihydropyrazino[2,3-b]pyrazin-6-one
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (5.95 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 20.0 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 mg/mL (5.95 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 20.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.9731 mL | 14.8655 mL | 29.7309 mL | |
| 5 mM | 0.5946 mL | 2.9731 mL | 5.9462 mL | |
| 10 mM | 0.2973 mL | 1.4865 mL | 2.9731 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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