Chk1 (Checkpoint kinase 1), an important serine/threonine kinase, is responding to DNA damage and stall DNA replication. Chk1 plays a key role in maintaining the replication fork viability during exposure to DNA antimetabolites. Inhibition of Chk1 will lead to accumulation of double-strand DNA breaks and cell death in human tumor cell lines exposure to antimetabolite. GDC-0575 is a selective Chk1 inhibitor with IC50 value of 1.2 nM. GDC-0575 exhibited anti-proliferative effect on nine of ten soft-tissue sarcoma (STS) cell lines with IC50 values ranging in 0.025-5.9μM, with inhibition of the phosphorylation of Ser296 observed. GDC-0575 could synergy with gemcitabine. It abrogated DNA damage-induced S and G2–M checkpoints exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Combined therapy of GDC-0575 (25mg/kg, orally) with gemcitabine twice a week for 3 weeks significantly reduced tumor growth increased progression-free survival of a P53mut UPS PDX model. GDC-0575 could enhance AraC-mediated killing of AML cells both in vitro and in vivo with abrogation of any potential chemoresistance mechanisms involving DNA repair.
作用机制
GDC-0575 is an ATP-competitive CHK1 inhibitor.
GDC-0575 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Primary AML cells
100 nM
1 week
To study the killing effect of GDC-0575 in combination with AraC on primary AML cells. Results showed that the combination treatment significantly reduced AML cell survival but had little effect on the frequency of long-term culture-initiating cells (L-LTC-IC).
Nat Commun. 2017 Nov 22;8(1):1679.
AML cell lines (HL60, KG-1, ML1, U937)
100 nM
24 hours
To evaluate the cytotoxic and apoptosis-inducing effects of GDC-0575 in combination with AraC on AML cell lines. Results showed that GDC-0575 significantly enhanced the killing effect of AraC on AML cells and increased apoptosis.
Nat Commun. 2017 Nov 22;8(1):1679.
N2a/APP cells
0.2, 0.5, 1 μM
24 hours
GDC-0575 dose-dependently reduced Chk1 protein levels, significantly decreased CIP2A levels and tau phosphorylation (at Ser199, Ser396, and AT8 sites) and APP levels
Neurotherapeutics. 2022 Mar;19(2):570-591.
HEK293/tau cells
0.2, 0.5, 1 μM
24 hours
GDC-0575 dose-dependently reduced Chk1 protein levels, significantly decreased CIP2A levels and tau phosphorylation (at Ser199, Ser396, and AT8 sites) and APP levels
Neurotherapeutics. 2022 Mar;19(2):570-591.
TC71 cells
1 μM
4 hours
To evaluate the effect of GDC-0575 on TC71 cell growth, results showed that GDC-0575 significantly inhibited cell growth.
Mol Cancer Res. 2020 Jan;18(1):91-104.
EW8 cells
1 μM
4 hours
To evaluate the effect of GDC-0575 on EW8 cell growth, results showed that GDC-0575 significantly inhibited cell growth.
Mol Cancer Res. 2020 Jan;18(1):91-104.
U2OS cells
300 nM
Used to study the role of ATR and CHK1 in transcriptional inhibition induced by rDNA breaks
Nat Commun. 2020 Jan 8;11(1):123.
GDC-0575 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG mice
AML xenograft model
Oral gavage
7.5 mg/kg
Every other day for 7 days
To evaluate the therapeutic effect of GDC-0575 in combination with AraC on AML xenograft models. Results showed that the combination treatment significantly reduced leukemic burden and delayed disease relapse. Additionally, the combination did not generate new mutations and may prevent the survival of AraC-induced mutagenic clones.
Nat Commun. 2017 Nov 22;8(1):1679.
C57 mice
DSS-induced acute colitis model and AOM/DSS-induced CAC model
Oral
7.5 mg/kg
Administered on days 15, 17, 19, and 21 post AOM injection
GDC-0575 significantly inhibited CHK1 expression in the colon and dramatically impaired the development of CAC and colitis in mice. Moreover, the inhibition of CHK1 expression resulted in efficient inhibition of infiltration by iNOS-positive macrophages, but had no significant effect on CD4 T cells, CD8 T cells, and myeloid-derived suppressor cells (MDSCs). Significant downregulation of TNF-α, IL-6, and IL-1β and dramatic upregulation of IL-10 were observed in the colons of both mice with CAC and colitis treated with GDC-0575. CCL2 expression was also downregulated by GDC-0575 in both mice with CAC and colitis; this was followed by the inhibition of CCR2+ macrophage infiltration in the colon.
Onco Targets Ther. 2021 Apr 15;14:2661-2672
APP/PS1 transgenic mice
Alzheimer's disease model
Oral gavage
25 mg/kg
Twice a week for 3 weeks
GDC-0575 treatment significantly inhibited Chk1 activity in the brains of APP/PS1 mice, reversed CIP2A upregulation, tau hyperphosphorylation and Aβ overproduction, ameliorated cognitive deficits, and prevented neuron loss and synaptic impairments
Neurotherapeutics. 2022 Mar;19(2):570-591.
GDC-0575 实验方案
计算器
存储液制备
1mg
5mg
10mg
1 mM
5 mM
10 mM
2.64mL
0.53mL
0.26mL
13.22mL
2.64mL
1.32mL
26.44mL
5.29mL
2.64mL
GDC-0575 技术信息
CAS号
1196541-47-5
分子式
C16H20BrN5O
分子量
378.27
SMILES Code
O=C(C1CC1)NC2=CNC3=NC=C(Br)C(N4C[C@H](N)CCC4)=C32
MDL No.
MFCD29048675
别名
ARRY-575; RG7741
运输
蓝冰
InChI Key
BAZRWWGASYWYGB-SNVBAGLBSA-N
Pubchem ID
46917793
存储条件
In solvent-20°C:3-6个月-80°C:12个月
Pure formKeep in dark place, inert atmosphere, 2-8°C
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