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.
CC-115 细胞实验
Cell Line
Concentration
Treated Time
Description
References
C4-2B
1 μM
24 h
reduced invasion and migration of CRPC cells
Clin Cancer Res. 2019 Sep 15;25(18):5608-5622.
LNCaP-AR
1 μM
24 h
reduced invasion and migration of CRPC cells
Clin Cancer Res. 2019 Sep 15;25(18):5608-5622.
Multiple myeloma cells
1.5 nM - 10 µM
72 h
CC-115 showed dose-dependent growth inhibition in multiple myeloma cells, and its effect was superior to the specific TORK inhibitor CC-223.
Mol Oncol. 2023 Feb;17(2):284-297.
HCT 116 cells
0.1 µM to 3.5 µM
4 h
CC-115 induced a dose-dependent increase in NMD transcripts in HCT 116 cells, indicating inhibition of SMG1-mediated NMD.
Mol Oncol. 2023 Feb;17(2):284-297.
CAL33
1 µM
24 h
CC-115 + IR treatment led to an elevation in G2/M arrest, increased cell death, and a synergistic reduction in cell proliferation, though the effect was notably lower compared to the AZD7648 + IR- treated group.
Cells. 2024 Feb 6;13(4):304.
UM-SCC-47
1 µM
24 h
CC-115 + IR treatment led to an elevation in G2/M arrest, increased cell death, and a synergistic reduction in cell proliferation, though the effect was notably lower compared to the AZD7648 + IR- treated group.
Cells. 2024 Feb 6;13(4):304.
LNCaP-AR-enza-res
1 μM
24 h
reduced invasion and migration of enzalutamide-resistant CRPC cells
Clin Cancer Res. 2019 Sep 15;25(18):5608-5622.
C4-2
0–25 μM
6 days
Assessment of CC-115 in hormone-sensitive and castration-resistant prostate cancer models showed that CC-115 reduced cell viability in a dose-dependent manner and induced apoptosis.
Clin Cancer Res. 2019 Sep 15;25(18):5623-5637.
22Rv1
0–25 μM
6 days
Assessment of CC-115 in hormone-sensitive and castration-resistant prostate cancer models showed that CC-115 reduced cell viability in a dose-dependent manner and induced apoptosis.
Clin Cancer Res. 2019 Sep 15;25(18):5623-5637.
Healthy donor skin fibroblasts (SBLF7)
0.1–25 μM
48 h
To study the effect of CC-115 on cell death, results showed that cell death increased linearly with increasing concentration of CC-115.
Int J Mol Sci. 2020 Dec 7;21(23):9321.
Melanoma cells (ARPA)
0.1–25 μM
48 h
To study the effect of CC-115 on cell death, results showed that melanoma cells were more sensitive to CC-115, with cell death reaching saturation at higher concentrations.
Int J Mol Sci. 2020 Dec 7;21(23):9321.
Melanoma cells (HV18MK)
0.1–25 μM
48 h
To study the effect of CC-115 on cell death, results showed that melanoma cells were more sensitive to CC-115, with cell death reaching saturation at higher concentrations.
Int J Mol Sci. 2020 Dec 7;21(23):9321.
LOU-NH91
25.10 μM
72 h
Assessed the IC50 value of CC-115 on LOU-NH91 cells, showing synergistic effects with carboplatin
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
H596
0.68 μM
72 h
Assessed the IC50 value of CC-115 on H596 cells, showing synergistic effects with carboplatin
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
H1975
0.31 μM
72 h
Assessed the IC50 value of CC-115 on H1975 cells, showing synergistic effects with carboplatin
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
TM00244
0.43 μM
72 h
Assessed the IC50 value of CC-115 on TM00244 cells, showing synergistic effects with carboplatin
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
H226
0.95 μM
72 h
Assessed the IC50 value of CC-115 on H226 cells, showing synergistic effects with carboplatin
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
Calu-1
1.38 μM
72 h
Assessed the IC50 value of CC-115 on Calu-1 cells, showing synergistic effects with carboplatin
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
Atmfl/fl; LSL-KrasG12D/+; Ptf1aCre/+ (AKC) cells
30 nM
6 h
To evaluate the effect of CC-115 on DNA replication dynamics
Gut. 2021 Apr;70(4):743-760.
ATM+/Δ MIA PaCa-2 cells
30 nM
48 h
To evaluate the synergistic effect of CC-115 in combination with PARPi and ATRi
Gut. 2021 Apr;70(4):743-760.
LOU-NH91
0.2 μM
72 h
CC-115 in combination with carboplatin showed synergistic effects in LOU-NH91 cells, significantly inhibiting cell viability.
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
Calu-1
0.4 μM
72 h
CC-115 in combination with carboplatin showed synergistic effects in Calu-1 cells, significantly inhibiting cell viability.
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
H226
0.4 μM
72 h
CC-115 in combination with carboplatin showed synergistic effects in H226 cells, significantly inhibiting cell viability.
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
CC-115 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Multiple myeloma xenograft model
Oral
5 mg/kg
Once daily until day 36
CC-115 showed significant antitumor activity in the multiple myeloma xenograft model, with a significant reduction in tumor volume and good tolerability.
Mol Oncol. 2023 Feb;17(2):284-297.
CB17-SCID mice
LNCaP-AR xenograft model
Oral
2 mg/kg
5 times per week for 6 weeks
Significantly delayed tumor growth
Clin Cancer Res. 2019 Sep 15;25(18):5608-5622.
CB17 SCID mice
Castration-resistant prostate cancer model
Oral
2 mg/kg
Once daily for 39 days
Evaluation of the tumor growth inhibitory effects of CC-115 in combination with Enzalutamide in castration-resistant prostate cancer models showed that the combination treatment significantly increased tumor doubling time and improved survival rates.
Clin Cancer Res. 2019 Sep 15;25(18):5623-5637.
Mice
LUSC PDX models
Oral gavage and I.P. injection
1 mg/kg
Once weekly for four weeks
Evaluated the antitumor effect of CC-115 in combination with carboplatin and paclitaxel on LUSC PDX models, showing significant tumor growth inhibition and prolonged survival
Mol Cancer Ther. 2022 Sep 6;21(9):1381-1392.
Mice
Subcutaneous tumor model
Intraperitoneal injection
2.5 mg/kg
Once daily for 17 days
To evaluate the inhibitory effect of CC-115 in combination with PARPi and ATRi on the growth of ATM-deficient PDAC tumors
Gut. 2021 Apr;70(4):743-760.
Mice
LUSC patient-derived xenograft models
Oral gavage (CC-115), Intraperitoneal injection (carboplatin and paclitaxel)
1 mg/kg
Once weekly (carboplatin and paclitaxel), daily (CC-115), for four weeks
CC-115 in combination with carboplatin and paclitaxel significantly inhibited tumor growth and extended survival in mice.
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