ETP-46464

• CAT Number: I001318
• CAS Number: 1345675-02-6
• Molecular Formula: C₃₀H₂₂N₄O₂
• Molecular Weight: 470.52
• Purity: ≥95%
• Synonyms: 2-methyl-2-[4-(2-oxo-9-quinolin-3-yl-4H-[1,3]oxazino[5,4-c]quinolin-1-yl)phenyl]propanenitrile
• Target: DNA-PK
• Solubility: DMSO 6 mg/ml; Water <1 mg/ml
• Storage: Store at -20C
• IC50: 0.6 nM (mTOR); 14 nM (ATR)
• InChI: InChI=1S/C30H22N4O2/c1-30(2,18-31)23-8-10-24(11-9-23)34-28-22(17-36-29(34)35)16-33-27-12-7-19(14-25(27)28)21-13-20-5-3-4-6-26(20)32-15-21/h3-16H,17H2,1-2H3
• InChIKey: DPLMXAYKJZOTKO-UHFFFAOYSA-N
• SMILES: CC(C)(C#N)C1=CC=C(C=C1)N2C3=C4C=C(C=CC4=NC=C3COC2=O)C5=CC6=CC=CC=C6N=C5

ETP-46464（Cat No.:I001318）is a potent and selective inhibitor of the DNA damage response kinase ataxia-telangiectasia and Rad3-related protein (ATR), a key regulator of the cellular response to DNA replication stress. By inhibiting ATR, ETP-46464 impairs the repair of DNA damage, leading to increased sensitivity of cancer cells to DNA-damaging agents, such as chemotherapy and radiation. This makes it a valuable tool in cancer research, particularly for exploring combination therapies targeting tumors with high replication stress or defective DNA repair mechanisms. ETP-46464 is studied for its potential to enhance cancer treatment efficacy.

Reference

[1]. Toledo, Luis I.; Murga, Matilde; Zur, Rafal; et al. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nature Structural & Molecular Biology (2011), 18(6), 721-727.
Abstract
Oncogene activation has been shown to generate replication-born DNA damage, also known as replicative stress. The primary responder to replicative stress is not Ataxia-Telangiectasia Mutated (ATM) but rather the kinase ATM and Rad3-related (ATR). One limitation for the study of ATR is the lack of potent inhibitors. We here describe a cell-based screening strategy that has allowed us to identify compounds with ATR inhibitory activity in the nanomolar range. Pharmacological inhibition of ATR generates replicative stress, leading to chromosomal breakage in the presence of conditions that stall replication forks. Moreover, ATR inhibition is particularly toxic for p53-deficient cells, this toxicity being exacerbated by replicative stress-generating conditions such as the overexpression of cyclin E. Notably, one of the compounds we identified is NVP-BEZ235, a dual phosphatidylinositol-3-OH kinase (PI3K) and mTOR inhibitor that is being tested for cancer chemotherapy but that we now show is also very potent against ATM, ATR and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs).