CC-115 hydrochloride is a potent dual inhibitor of DNA-PK (IC50 = 13 nM) and mTOR kinase (IC50 = 21 nM), effectively blocking both mTORC1 and mTORC2 signaling pathways.

mTOR:21 nM, DNA-PK:13 nM, PI3Kα:852 nM

CC-115 effectively inhibits the proliferation of PC-3 cells with an IC50 value of 138 nM. In kinase selectivity screenings at 3 μM against 250 protein kinases, it significantly inhibits only mTOR kinase and one other kinase, cFMS, by 57% (IC50 = 2.0 μM). Among the tested PI3K-related kinases (PIKKs), CC-115 shows equipotency to DNA PK with an IC50 of 15 nM, demonstrating a selectivity range of 40 to >1000 fold over other PIKKs such as PI3K-alpha (IC50 = 0.85 μM), ATR (50% inhibition at 30 μM), and ATM (IC50 >30 μM). Furthermore, CC-115 displays minimal inhibitory activity against CYP enzymes and the hERG ion channel with IC50 values exceeding 10 μM and 33 μM, respectively. In a screening against a Cerep receptor and enzyme panel at 10 μM, CC-115 notably inhibits only one target, PDE3, by more than 50% (IC50 = 0.63 μM) [1].

CC-115 hydrochloride demonstrates favorable pharmacokinetic (PK) profiles in vivo across multiple species, achieving oral bioavailability rates of 53%, 76%, and approximately 100% in mice, rats, and dogs, respectively. When administered at doses of 0.25, 0.5, and 1 mg/kg twice daily (bid) or at a single daily dose (qd) of 1 mg/kg, CC-115 leads to notable tumor volume reductions of 46%, 57%, 66%, and 57%, respectively. The compound maintains its inhibitory effect for 24 hours, with significant activity noted at 1 and 3 hours post-administration at a 1 mg/kg dose, and continuous inhibition observable up to 10 hours. CC-115 has been assessed under both once daily (qd) and twice daily (bid) dosing regimens.