VE-821 is a potent ATP-competitive inhibitor of ATR with K_i/IC₅₀ of 13 nM/26 nM.

VE-821 shows excellent selectivity for ATR with minimal cross-reactivity against the related PIKKs ATM, DNA-PK, mTOR and PI3Kγ (K_is of 16 μM, 2.2 μM, >1 μM and 3.9 μM, respectively) and against a large panel of unrelated protein kinases^[1]. VE-821 (compound 27) also inhibits ATM and DNA-PK wirh IC₅₀ of >8 μM, and 4.4 μM, respectively^[2]. VE-821 significantly enhances the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and Gemcitabine under both normoxic and hypoxic conditions. ATR inhibition by VE-821 leads to inhibition of radiation-induced G₂/M arrest in cancer cells. In both PSN-1 and MiaPaCa-2 cells, 1 µM VE-821 inhibits phosphorylation of Chk1 (Ser 345) after treatment with Gemcitabine (100 nM), radiation (6 Gy) or both, at 2 h post-irradiation^[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

368.41

C₁₈H₁₆N₄O₃S

1232410-49-9

Room temperature in continental US; may vary elsewhere.

Powder	-20°C	3 years
	4°C	2 years
In solvent	-80°C	6 months
	-20°C	1 month

In Vitro: 

DMSO : 50 mg/mL (135.72 mM; Need ultrasonic)

H₂O : < 0.1 mg/mL (ultrasonic;warming;heat to 60°C) (insoluble)

*

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。

In Vivo:

• 1.

  VE-821 is prepared im vehicle (10% PEG300, 2.5% Tween-80, pH 4)^[4].

• [1]. Reaper PM, et al. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011 Apr 13;7(7):428-30.

  [2]. Charrier JD, et al. Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem. 2011 Apr 14;54(7):2320-30.

  [3]. Prevo R, et al. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther. 2012 Sep;13(11):1072-81.

  [4]. Muralidharan SV, et al. BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells. Oncogene. 2016 Sep 8;35(36):4689-97.

The ability of compounds (e.g., VE-821) to inhibit ATR, ATM or DNAPK kinase activity is tested using a radiometric-phosphate incorporation assay. A stock solution is prepared consisting of the appropriate buffer, kinase, and target peptide. To this is added the compound of interest, at varying concentrations in DMSO to a final DMSO concentration of 7%. Assays are initiated by addition of an appropriate [g-³³P]ATP solution and incubated at 25°C. Assays are stopped, after the desired time course, by addition of phosphoric acid and ATP to a final concentration of 100 mM and 0.66 μM, respectively. Peptides are captured on a phosphocellulose membrane, prepared, and washed six times with 200 μL of 100 mM phosphoric acid, prior to the addition of 100 μL of scintillation cocktail and scintillation counting on a 1450 Microbeta Liquid Scintillation Counter. Dose−response data are analyzed using GraphPad Prism software^[2].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

MiaPaCa-2, PSN-1 and Panc1 cells (5×10⁴) are plated in 96-well plates and after 4 h treated with increasing concentrations of VE-821 at 1 h before irradiation with a single dose of 4 Gy. Medium is replaced 72 h post-irradiation at which point viability is measured using the using the Alamar Blue assay. Cells are allowed to proliferate and cell viability is again analyzed at day 10 for the different treatment conditions. Cell viability and surviving fraction are normalized to the untreated (control) group^[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

• [1]. Reaper PM, et al. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol. 2011 Apr 13;7(7):428-30.

  [2]. Charrier JD, et al. Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem. 2011 Apr 14;54(7):2320-30.

  [3]. Prevo R, et al. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther. 2012 Sep;13(11):1072-81.

  [4]. Muralidharan SV, et al. BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc-induced lymphoma cells. Oncogene. 2016 Sep 8;35(36):4689-97.