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.
CAS Number: 1228013-15-7
Molecular Weight: 336.35
Chemical 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
Appearance: Solid Power
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO, not in water
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥12 months if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
CC-115 inhibits PC-3 cells proliferation with an IC50 of 138 nM. In a kinase selectivity assessment against a panel of 250 protein kinases at 3 μM, only one kinase other than mTOR kinase is identified with more than 50% inhibition (cFMS 57%, IC50=2.0 μM). Of the PI3K related kinases (PIKKs) tested, CC-115 proves to be equipotent against DNA PK (IC50=15 nM) and demonstrates 40 to >1000 fold selectivity against the remaining PIKKs tested; PI3K-alpha (IC50=0.85 μM), ATR (50% inhibition at 30 μM) and ATM (IC50>30 μM). The IC50 values for CC-115 are >10 μM against a panel of CYP enzymes and >33 μM for the hERG (human ether-a-go-go-related gene) ion channel. When screened in a single point assay at 10 μM against a Cerep receptor and enzyme panel only one target is inhibited >50% (PDE3, IC50=0.63 μM).
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 is tested at lower doses of 0.25, 0.5 and 1 mg/kg bid or 1 mg/kg qd, with observed corresponding tumor volume reductions of 46%, 57%, 66% and 57% respectively. CC-115 sustains inhibition though 24 hours. At the 1 mg/kg dose CC-115 shows significant inhibition at 1 and 3 hours, CC-115 demonstrating inhibition through 10 hours. CC-115 is evaluated using both once (qd) and twice (bid) daily dosing schedules.
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