CC-115 is a dual inhibitor of mammalian target of rapamycin kinase (mTOR) and DNA-dependent protein kinase (DNA-PK), two members in the PI3K family. It inhibits TORK and DNA-PK with IC50 values of 0.021 and 0.013 µM, respectively[3]. In primary chronic lymphocytic leukemia (CLL) cells, CC-115 at 0.1-0.35 µM dose-dependently suppressed Ser-2056 phosphorylation on DNA-PK and bleomycin-induced Ser-1981 phosphorylation on ATM. CC-115 at 1 µM significantly inhibited irradiation (5 Gy)-induced γH2AX level in ATM/11q mutated CLL cells. Low dose CC-115 (0.35 µM) successfully blocked the constitutive phosphorylation of S6, a marker for mTORC1 activity, in all CLL cells. It also completely inhibited the phosphorylation of the mTORC1 and mTORC1 targets in BCR-stimulated CLL cells at the concentration of 1 µM. CC-115 induced caspase-dependent cell death in resting CLL cells with an IC50 value of 0.51 µM. CC-115 at the dose of 1 µM reverted CD40-mediated resistance to chemotherapy or venetoclax in CLL cells cultured on CD40L-expressing fibroblasts. CC-115 treatment (1 µM) also efficiently inhibited the proliferation of CLL cells[4]. In PC-3 tumor-bearing mice, administration of CC-115 at 0.25, 0.5 and 1 mg/kg twice daily or 1 mg/kg once daily resulted in the tumor volume reduction of 46%, 57%, 66% and 57%, respectively.
作用机制
CC-115 inhibits both mTOR and DNA-PK by extending the 7-substituent into the kinase catalytic pocket to inhibit their activities.
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