3-Amino-6-[4-(methylsulfonyl)phenyl]-N-phenyl-2-pyrazinecarboxamide

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 (IC₅₀ = 26 nM). It augments DNA damage and cell death of cancer cells in response to radiation under normal and hypoxic conditions. VE-821 also sensitizes cancer cells to chemotherapy.

Chemical Properties

Bright Yellow Solid

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.

Synthesis

A reaction was carried out with 3-amino-6-(4-methylsulfonylphenyl)pyrazine-2-carboxylic acid (1.5 g, 5.114 mmol), diethoxyphosphonocarbonitrile (926.8 mg, 849.5 μL, 5.114 mmol), aniline (476.2 mg, 465.9 μL, 5.114 mmol) and triethylamine (1.035 g, 1.426 mL. 10.23 mmol) were used as raw materials, and the reaction was stirred in DME (18.75 mL) at 120 °C for 18 hours. Upon completion of the reaction, water was added and the resulting solid was collected by filtration. The resulting solid was ground with acetone and dried to afford the target compound 3-amino-6-[4-(methylsulfonyl)phenyl]-N-phenyl-2-pyrazinecarboxamide (1.335 g, 71% yield). The product was characterized by 1H NMR (400.0 MHz, DMSO): δ 3.28 (s, 3H), 7.18 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.82 (d, J = 7.9 Hz, 2H), 7.89 (s, 2H), 8.01 (d, J = 8.4 Hz, 2H), 8.51 ( d, J = 8.4 Hz, 2H), 9.04 (s, 1H), 10.47 (s, 1H) ppm; mass spectrum (ES+) m/z 369.

storage

Store at -20°C

References

[1] PHILIP M REAPER. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR[J]. Nature chemical biology, 2011, 7 7: 428-430. DOI:10.1038/nchembio.573
[2] REMKO PREVO. The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy.[J]. Cancer Biology & Therapy, 2012, 13 11: 1072-1081. DOI:10.4161/cbt.21093
[3] CATHERINE J HUNTOON. ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status.[J]. Cancer research, 2013: 3683-3691. DOI:10.1158/0008-5472.can-13-0110
[4] DAVID KING. Increased Replication Stress Determines ATR Inhibitor Sensitivity in Neuroblastoma Cells.[J]. Cancers, 2021. DOI:10.3390/cancers13246215
[5] BENCHAMART MOOLMUANG  Mathuros R. 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]. Journal of Pharmacy and Pharmacology, 2021, 73 1: 40-51. DOI:10.1093/jpp/rgaa050