CCT245737, at a concentration of 10 µM, demonstrates significant inhibition (>80%) across a wide panel of 124 kinases, notably including ERK8, PKD1, RSK2, and RSK1, with IC50 values of 130, 298, 361, and 362 nM, respectively[1]. CCT245737 effectively disrupts the G2 checkpoint induced by VP-16 in various cell lines such as HT29, SW620, MiaPaCa-2, and Calu6, showcasing IC50 values ranging from 30 to 220 nM[2].
体内研究
When administered orally at 150 mg/kg, CCT245737 synergizes with LY 188011 (intravenously at 100 mg/kg) to inhibit tumor growth in HT29 colon cancer xenograft models. Furthermore, a dose of 300 mg/kg orally inhibits CHK1 autophosphorylation at Ser296 induced by LY 188011 (60 mg/kg intravenously) in SW620 colon cancer xenografts 24 hours post-treatment[1].
CCT245737, at 150 mg/kg orally, also markedly suppresses tumor growth in an Eμ-Myc mouse model of human B-cell lymphocytic leukemia[2].
体外研究
CCT245737, at a concentration of 10 µM, demonstrates significant inhibition (>80%) across a wide panel of 124 kinases, notably including ERK8, PKD1, RSK2, and RSK1, with IC50 values of 130, 298, 361, and 362 nM, respectively[1].
CCT245737 effectively disrupts the G2 checkpoint induced by VP-16 in various cell lines such as HT29, SW620, MiaPaCa-2, and Calu6, showcasing IC50 values ranging from 30 to 220 nM[2].
作用机制
CCT245737 binds in the ATP pocket of human CHK1. It is an ATP competitive inhibitor.
CCT245737 细胞实验
Cell Line
Concentration
Treated Time
Description
References
H1694 and H847 cells
1μM
72 hours
To evaluate the activation of the STING pathway by SRA737, showing time-dependent activation.
J Thorac Oncol. 2019 Dec;14(12):2152-2163.
H69 and H446 cells
1μM
24 hours
To assess SRA737-induced micronuclei formation, showing a significant increase in MN frequency.
J Thorac Oncol. 2019 Dec;14(12):2152-2163.
SCLC cell lines
10μM
96 hours
To evaluate the antiproliferative activity of SRA737 on SCLC cell lines, showing a range of sensitivities to SRA737.
J Thorac Oncol. 2019 Dec;14(12):2152-2163.
SW620 colorectal cancer cells
0.8 μM
84 hours
Evaluate the sensitivity of SW620 cells to the CHK1 inhibitor SRA737, showing that knockdown of POLA1 and POLE2 significantly increased cell sensitivity to SRA737.
Cancer Res. 2020 Apr 15;80(8):1735-1747.
A549 non-small cell lung cancer cells
0.4 μM
84 hours
Evaluate the sensitivity of A549 cells to the CHK1 inhibitor SRA737, showing that knockdown of POLA1, POLE, and POLE2 significantly increased cell sensitivity to SRA737.
Cancer Res. 2020 Apr 15;80(8):1735-1747.
SW620
3 μM
6 h
Evaluate the effect of CCT245737 in resistant cells. Results showed that CCT245737 at 3 μM concentration inhibited 50% of pS296-CHK1.
ACS Pharmacol Transl Sci. 2021 Feb 12;4(2):730-743.
AsPC-1
1 μM
6 h
Evaluate the inhibitory effect of CCT245737 on CHK1. Results showed that CCT245737 at 1 μM concentration inhibited 50% of pS296-CHK1.
ACS Pharmacol Transl Sci. 2021 Feb 12;4(2):730-743.
MDA-MB-231 cells
0.1-1 μg/mL
12 hours
Evaluate cytotoxicity of SRA737 and DOX, results showed SRA737 significantly enhanced DOX cytotoxicity
Int J Mol Sci. 2022 Jul 20;23(14):7981.
PEO1-PR cells
0.2 μM
24 hours
To evaluate the effect of SRA737 on PARPi-resistant cells, results showed that SRA737 increased the expression of p-CHK1 (S345)
iScience. 2024 May 15;27(7):109978.
OVCAR3 cells
0.2 μM
24 hours
To evaluate the effect of SRA737 on replication stress and DNA double-strand breaks, results showed that SRA737 increased the expression of p-CHK1 (S345) and γ-H2AX
iScience. 2024 May 15;27(7):109978.
OVCAR3 cells
100 nM
12 days
To assess the activity of SRA737 monotherapy in CCNE1 amplified HGSOC, results showed that 100 nM SRA737 inhibited more than 50% of colony area
iScience. 2024 May 15;27(7):109978.
Mammary carcinoma cells (SUM149)
0.25 μM
24 hours
Evaluate the cytotoxic effects of SRA737 in combination with niraparib, showing that the combination led to cell death.
Cancer Biol Ther. 2018;19(9):786-796.
Ovarian cancer cells (Spiky)
0.25 μM
24 hours
Evaluate the cytotoxic effects of SRA737 in combination with niraparib, showing that the combination led to cell death.
Cancer Biol Ther. 2018;19(9):786-796.
Mammary carcinoma cells (BT474)
0.25 μM
24 hours
Evaluate the cytotoxic effects of SRA737 in combination with niraparib, showing that the combination led to cell death.
Cancer Biol Ther. 2018;19(9):786-796.
MDA-MB-436
1819 nM (SRA737) and 546 nM (adavosertib)
24 hours
Assessed cell cycle distribution, replication stress, apoptosis, and DNA double-strand breaks. Results showed a significant increase in S-phase cells (66.5% vs 23.7%) and elevated levels of p-CHK1Ser345, c-PARP, and γH2AX compared to control.
BJC Rep. 2024 Apr 3;2(1):27.
OVCAR3
730 nM (SRA737) and 182 nM (adavosertib)
24 hours
Assessed cell cycle distribution, replication stress, apoptosis, and DNA double-strand breaks. Results showed a significant increase in S-phase cells (50.5% vs 21%) and elevated levels of p-CHK1Ser345, c-PARP, and γH2AX compared to control.
BJC Rep. 2024 Apr 3;2(1):27.
K562 cells
500 nM
24 hours
CCT245737 significantly inhibited CHK1 autophosphorylation at Ser296, promoted the accumulation of DNA damage, and enhanced the cytotoxicity of VP16 in K562 cells
Oncol Rep. 2020 Nov;44(5):2152-2164.
CCT245737 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
B6129F1 mice
RPP xenograft model
Oral
100mg/kg
5 days on/2 days off
To evaluate the antitumor activity of SRA737 alone or in combination with anti-PD-L1, showing significant tumor growth inhibition with the combination.
J Thorac Oncol. 2019 Dec;14(12):2152-2163.
Mice
TRAMP mouse model
Oral
60 mg/kg (AZD1775), 100 mg/kg (SRA737)
5 days-on / 2 days-off for four weeks
AZD1775 or SRA737 alone not only completely blocked tumor growth but also resulted in tumor regression
Oncogene. 2024 Mar;43(11):789-803.
Mice
Subcutaneous OVCAR3 tumor model
Oral
25, 50, 100 or 150 mg/kg
Once daily for 5 days, 2 days off, for 3 cycles
To evaluate the anti-tumor efficacy of SRA737 monotherapy in CCNE1 amplified tumors, results showed significant tumor growth inhibition in the 100 and 150 mg/kg dose groups
iScience. 2024 May 15;27(7):109978.
Athymic mice
BT474 mammary tumor model
Oral
25 mg/kg
Once daily for 5 days
Evaluate the anti-tumor effects of SRA737 in combination with niraparib, showing that the combination significantly suppressed tumor growth.
Cancer Biol Ther. 2018;19(9):786-796.
NSG mice
OVCAR3 and MDA-MB436 xenograft models
Oral
120 mg/kg QD
2 consecutive days/7 ×3 weeks
Evaluated the tumor growth inhibitory effects of the combination. Results showed significant tumor regression in the OVCAR3 model (p<0.0001) with TGI of 107.9%, and significant reduction in tumor volume in the MDA-MB-436 model (p=0.0025) with TGI of 44.7%.
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