CC-115 hydrochloride 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 the proliferation induced by CD40(+) interleukin-21 stimulation could be completely blocked by CC-115, and CD40-mediated resistance to fludarabine and venetoclax could also be reverted by CC-115. Moreover, BCR-mediated signaling was blocked by CC-115 and in CLL samples from patients with acquired resistance to idelalisib treatment.
理化性质和储存条件
| Molecular Weight (MW) | 372.81 |
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| Formula | C16H17ClN8O |
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| CAS No. | 1300118-55-1 (HCl) |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO:>67 mg/mL (199.2 mM) |
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| Water: N/A |
| Ethanol: N/A |
| SMILES Code | SMILES Code: [H]Cl.O=C1CN=C2C(N1CC)=NC(C3=C(C)N=C(C4=NN=CN4)C=C3)=CN2 |
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| Synonyms | CC115 HCl; CC-115; CC 115 hydrochloride; 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one hydrochloride |
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实验参考方法
| In Vitro | In vitro activity: CC-115 inhibits the DNA damage repair pathway and TORK in CLL cells and induces caspase-dependent cell death in resting CLL cells. It induces cell death with an IC50 of 0.51 μM. CC-115 reverts CD40-induced chemoresistance. CC-115 treatment significantly reduces induction of expression Mcl-1, Bfl-1, and Bcl-XL on CD40 stimulation in CLL cells. It also blocks proliferation of CLL cells. In healthy B cells, CC-115 induces cell death with an IC50 of 0.93 μM. CC-115 and NU7441 completely block the proliferation of CD4+ and CD8+ T cells. Taken together, CC-115 induces direct cytotoxicity and can block signaling pathways that are important for CLL survival, chemo-resistance and proliferation in the in the LN microenvironment.
Kinase Assay: An HTR-FRET substrate phosphorylation assay is employed for mTOR kinase. PI3Kα IC50 determinations are outsourced using the mobility shift assay format. Compounds (e.g., CC-115) are assessed against concentrations of ATP at approximately the Km for the assay, with average ATP Km of 15 μM and 50 μM for the mTOR and PI3K assays, respectively.
Cell Assay: Freshly isolated CLL cells are treated with different concentrations of CC-115 for 30 minutes. Subsequently, the cells are exposed to 5-Gy γ-radiation or treated with 10 μg/mL bleomycin (EMD Millipore, Billerica, MA) and incubated for 30 minutes, and cell lysates are made. |
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| In Vivo | CC-115 decreases lymphadenopathy in CLL patients. CC-115 shows good in vivo PK profiles across multiple species with 53%, 76%, and ~100% oral bioavailability in mouse, rat, and dog, respectively. CC-115 has favorable physicochemical and pharmacokinetic properties, demonstrates in vivo mTOR pathway inhibition and tumor growth inhibition, as well as a good in vitro and in vivo safety profile, suitable for clinical development. |
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| Animal model | Mice |
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| Formulation & Dosage | CC-115 is advanced into single dose PK/PD studies assessing mTOR pathway biomarker inhibition in tumor bearing mice. PC-3 tumor-bearing mice are administered with a single dose of CC-115, dosed orally at either 1 or 10 mg/kg, and plasma and tumor samples are collected at various time points for analysis. Significant inhibition of both mTORC1 (pS6) and mTORC2 (pAktS473) is observed for all compounds and the level of biomarker inhibition correlated to plasma compound levels. |
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| References | Blood. 2016 Jul 28;128(4):574-83; J Med Chem. 2015 Jul 23;58(14):5599-608. |
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