Chemical Properties
Bright Yellow Solid
Usage
VE 821 is a potent and selective inhibitor of DNA damage response kinase, ATR. VE 821 functions to disrupt DNA damage repair system of tumor cells, limiting their abilities for further growth.
Description
Ataxia-telangiectasia and Rad3-related protein (ATR) is a serine/threonine kinase that activates DNA processes related to the DNA damage response. VE-821 is an ATP-competitive inhibitor of ATR (IC
50 = 26 nM).
1,2 It augments DNA damage and cell death of cancer cells in response to radiation under normal and hypoxic conditions.
2,3,4 VE-821 also sensitizes cancer cells to chemotherapy.
3,5,6
Uses
VE-821 has been used as an inhibitor of ATM- and Rad3-related (ATR) protein in human cancer cells.
Uses
VE 821 is a potent and selective inhibitor of DNA damage response kinase, ATR. VE 821 functions to disrupt DNA damage repair system of tumor cells, limiting their abilities for further growth.
Definition
ChEBI: 3-amino-6-(4-methylsulfonylphenyl)-N-phenyl-2-pyrazinecarboxamide is an aromatic amide.
Biochem/physiol Actions
VE-821 is a potent ATP-competitive inhibitor of the DNA damage response (DDR) kinase Ataxia telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) with a Ki of 13 nM. VE-821 has minimal cross-reactivity against the related PIKKs ATM, DNA-dependent protein kinase (DNA-PK), mTOR and PI3-kinase-γ (Ki of 16 μM, 2.2 μM, >1 μM and 3.9 μM, respectively) and against a large panel of unrelated protein kinases. VE-821 used alone caused death in a large fraction of cancer cell populations and also showed strong synergy with genotoxic agents. VE-821 increased sensitivity of cells to radiation and also sensitized cancer cells to a variety of chemotherapeutic agents.
References
Reaper et al. (2011), Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR; Nat. Chem. Biol., 7 428
Prevo et al. (2012), The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy; Cancer Biol. Ther., 13 1072
Huntoon et al. (2013), ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status; Cancer Res., 73 3683
King et al. (2021), Increased Replication Stress Determines ATR Inhibitor Sensitivity in Neuroblastoma Cells; Cancers (Basel), 13 6215
Moolmuang and Ruchirawat (2021), The antiproliferative effects of ataxia-telangiectasia mutated and ATM- and Rad3-related inhibitions and their enhancements with the cytotoxicity of DNA damaging agents in cholangiocarcinoma cells; J. Pharm. Pharmacol., 73 40
