Catalog Number
ACM1228013157
Description
CC-115 is a dual inhibitor of DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR), with potential antineoplastic activity. CC-115 binds to and inhibits the activity of DNA-PK and both raptor-mTOR (TOR complex 1 or TORC1) and rictor-mTOR (TOR complex 2 or TORC2), which may lead to a reduction in cellular proliferation of cancer cells expressing DNA-PK and TOR. DNA-PK, a serine/threonine kinase and a member of the PI3K-related kinase subfamily of protein kinases, is activated upon DNA damage and plays a key role in repairing double-stranded DNA breaks via the DNA nonhomologous end joining (NHEJ) pathway.
Synonyms
CC115 ; CC-115; CC 115
IUPAC Name
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
Molecular Formula
C16H16N8O
Canonical SMILES
O=C1CNC2=NC=C(C3=CC=C(C4=NC=NN4)N=C3C)N=C2N1CC
InChI
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)
InChI Key
GMYLVKUGJMYTFB-UHFFFAOYSA-N
Solubility
Soluble in DMSO, not in water
Appearance
Red solid powder
Shelf Life
>5 years if stored properly
Storage
Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
Alternative CAS
1228013-15-7 (free base); 1300118-55-1 (HCl)
Biological Target
CC-115 is a potent and dual DNA-PK and mTOR kinase inhibitor with IC50s of 13 nM and 21 nM, respectively, that blocks both mTORC1 and mTORC2 signaling.
Drug Formulation
This drug may be formulated in DMSO
Elemental Analysis
C, 57.13; H, 4.79; N, 33.31; O, 4.76
HS Tariff Code
2934.99.9001
In Vitro Activity
To evaluate the impact of CC-115 inhibition of mTOR kinase and DNA-PK, CC-115 was tested in vitro across a panel of 123 cancer cell lines composed of 40 lymphoma and leukemia, 22 breast cancer, 11 hepatocellular carcinoma, 11 head and neck cancer, and 39 lung cancer cell lines. CC-115 has potent growth inhibitory activity against the majority of the cancer cell lines with GI50 values ranging from 0.015 μM to 1.77 μM (Figure2A2A and Supplementary Table 2). While selective inhibitors of mTOR kinase have been reported to primarily result in cell cycle arrest without significant induction of apoptosis in solid tumor lines, in a subset of both hematological and solid tumor cell lines, CC-115 induced strong apoptosis. CC-115 also inhibited NHEJ activity in a concentrationdependent manner. Partial inhibition was observed with 0.5 μM CC-115 treatment (lane 3) and 5 μM CC-115 achieved complete inhibition (lane 4). Therefore, CC-115 prevents NHEJ by blocking autophosphorylation of DNA-PKcs and dissociation of DNA-PKcs and the ligase IV/XLF/XRCC4 complex from the dsDNA end. This study suggests the use of ATM deficiency as a patient selection strategy for CC-115 as a single agent.
Reference: Oncotarget. 2017 Sep 26; 8(43): 74688-74702. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650372/
In Vivo Activity
The in vivo activity of CC-115 was tested. As described, 786-O cells were s.c. injected into the flanks of the nude mice. Xenografts were established within three weeks (tumor volumes close to 100 mm3, labeled as "Day-0"). The tumor-bearing mice were randomly assigned into three groups, receiving CC-115 or vehicle control. Results demonstrated that oral administration of CC-115, at 2 mg/kg or 5 mg/kg, significantly inhibited subcutaneous 786-O xenograft growth in nude mice (Figure 5A). The estimated daily 786-O tumor growth, calculated by (tumor volume at Day-30 subtracting tumor volume at Day-30)/30, was dramatically inhibited in CC-115treated mice (Figure 5B). Tumors of all three groups were isolated at Day-30 and weighted (Figure 5C). Tumors with CC-115 treatment were much lighter than the vehicle-treated tumors (Figure 5C). The mouse body weights were not significantly different between the three groups (Figure 5D). Collectively, oral administration of CC-115 inhibited subcutaneous 786-O xenograft growth in mice.
Reference: Aging (Albany NY). 2020 Oct 31; 12(20): 20445-20456. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655216/
Shipping
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Stock Solution Storage
0-4 °C for short term (days to weeks), or -20 °C for long term (months).
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