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) [1]
• 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)C(C=C1)=CC=C1N(C2=C(CO3)C=NC(C2=C4)=CC=C4C5=CC6=CC=CC=C6N=C5)C3=O

ETP-46464 is a cell-permeable quinoline-containing heterotricyclic compound that acts as a potent inhibitor against mTOR, ATR, DNA-PK, PI 3-Kα, and ATM (IC50= 0.6, 14, 36, 170, and 545 nM, respectively).IC50 Value: 0.6 nM (mTOR); 14 nM (ATR) [1]Target: ATR; mTORETP-46464 preferentially suppresses radiation-induced cellular ATR activity (>90% at 500 nM) over ATM or DNA-PK activity (IC50 > 5 uM) in U2OS cells, while exhibiting much reduced or little potency toward a panel of 26 other kinases (>55% inhibition at 5 uM). ETP-46464 is Shown to synergize with UCN-01 in replicative stress induction in S-phase replicating U2OS (1.5-, 61-, and 190-fold of control RS, respectively, with 1 uM ETP-46464, 50 nM UCN-01, or combined treatment).

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).