"目录号: HY-13902
Cell Cycle/DNA DamagePI3K/Akt/mTOR-
VE-822 是一种ATR抑制剂，Ki值 <0.2 nM，也抑制ATM，Ki为 34 nM。
ATM/ATR
相关产品
Wortmannin-AZD6738-VE-821-KU-55933-KU-60019-AZD0156-CP-466722-AZ20-CGK733-ETP-46464-HLM006474-BAY-1895344 hydrochloride-
生物活性
Description
VE-822 is anATRinhibitor withKivalue of <0.2 nM, also inhibitsATMwithKiof 34 nM.
IC50& Target
Ki: <0.2 nM (ATR), 34 nM (ATM)[1]
IC50: 19 nM (ATR, in PSN-1 and MiaPaCa-2 cells), 2.6 μM (ATM, in PSN-1 and MiaPaCa-2 cells)[1]
In Vitro
VE-822 also inhibits DNK-PA, mTOR, PI3Kγ with IC50of >4, >1, and 0.22 μM, respectively. In PSN-1 and MiaPaCa-2 cells, VE-822 inhibits ATR and ATM with IC50of 19 nM and 2.6 μM, respectively. VE-822 (80 nM) reduces phospho-Ser345-Chk1 after Gemcitabine (100 nM), radiation (XRT) (6 Gy) or both in PDAC. Additionally, VE-822 does not inhibit ATM, Chk2 or DNA-PK phosphorylation in response to radiation, which further supports the selectivity of VE-822 for ATR. VE-822 decreases survival of irradiated PDAC (all lines used are p53-mutant; K-Ras mutant). Knock down of Chk1 by siRNA sensitizes PSN-1 and MiaPaCa-2 cells to radiation but the radiosensitising effect is less profound compare with VE-822. Adding VE-822 to Gemcitabine reduces survival ~2-3-fold and dramatically more after chemoradiotherapy[1].
In Vivo
PSN-1 xenografts are treated with VE-822 (60 mk/kg; d0, 1), Gemcitabine (100 mg/kg; d0) and/or XRT (6 Gy; d1). Tumors are then harvested 2 h post-XRT. VE-822 inhibits p-Ser-345-Chk1 in xenografts after DNA-damaging agents, establishing VE-822 as a potent inhibitor of ATR in vivo. Besides, VE-822 enhances the therapeutic efficacy of radiation (XRT) in MiaPaCa-2 and PSN-1 xenograft models[1].
Clinical Trial
NCT02595931
National Cancer Institute (NCI)
Advanced Malignant Solid Neoplasm-Metastatic Malignant Neoplasm-Metastatic Malignant Solid Neoplasm-Refractory Malignant Neoplasm-Unresectable Malignant Neoplasm-Unresectable Solid Neoplasm
June 8, 2016
Phase 1
NCT02723864
National Cancer Institute (NCI)-National Institutes of Health Clinical Center (CC)
Neoplasms
March 22, 2016
Phase 1
NCT02589522
National Cancer Institute (NCI)
Lung Carcinoma Metastatic in the Brain-Stage IV Non-Small Cell Lung Cancer AJCC v7
July 21, 2016
Phase 1
NCT02567422
National Cancer Institute (NCI)
Head and Neck Squamous Cell Carcinoma-Human Papillomavirus Negative-Stage III Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v6 and v7-Stage III Oropharyngeal Squamous Cell Carcinoma AJCC v7-Stage IV Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7-Stage IV Oropharyngeal Squamous Cell Carcinoma AJCC v7-Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7-Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7-Stage IVB Nasal Cavity and Paranas
September 2, 2016
Phase 1
NCT02595892
National Cancer Institute (NCI)
Ovarian Serous Tumor-Recurrent Fallopian Tube Carcinoma-Recurrent Ovarian Carcinoma-Recurrent Primary Peritoneal Carcinoma
August 25, 2016
Phase 2
NCT02567409
National Cancer Institute (NCI)
Metastatic Urothelial Carcinoma of the Renal Pelvis and Ureter-Stage IV Bladder Urothelial Carcinoma
August 19, 2016
Phase 2
NCT02487095
National Cancer Institute (NCI)-National Institutes of Health Clinical Center (CC)
Carcinoma, Non-Small -Cell Lung-Ovarian Neoplasms-Small Cell Lung Carcinoma-Uterine Cervical Neoplasms-Carcinoma, Neuroendocrine
June 18, 2015
Phase 1-Phase 2
NCT02627443
National Cancer Institute (NCI)
High Grade Ovarian Serous Adenocarcinoma-Ovarian Endometrioid Tumor-Recurrent Fallopian Tube Carcinoma-Recurrent Ovarian Carcinoma-Recurrent Primary Peritoneal Carcinoma-Stage IV Fallopian Tube Cancer-Stage IV Ovarian Cancer-Stage IV Primary Peritoneal Cancer
November 4, 2016
Phase 1-Phase 2
NCT02157792
Vertex Pharmaceuticals Incorporated
Advanced Solid Tumor
December 2012
Phase 1
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References
[1].Fokas E, et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012 Dec 6;3:e441.